Marcelo Fernandez Vina - Stanford Profiles

Marcelo Fernandez Vina

Professor of Pathology

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Bio

Marcelo Fernández-Viña, Ph.D., D (ABHI) is a Professor for the Department of Pathology at Stanford University Medical School and serves as Director of the Histocompatibility, Immunogenetics and Disease Profiling Laboratory at this institution. He has been working in the fields of Histocompatibility and Immunogenetics since 1982. He earned a degree in Biochemistry from the School of Basic Sciences in Rosario, Argentina, and his Ph.D. in Internal Medicine from the University of Buenos Aires Medical School in Argentina. Previously he held a position as a Professor in the Department of Laboratory Medicine at the University of Texas M.D. Anderson Cancer Center in Houston. He has more than 180 peer reviewed publications, many of them focusing on HLA variation in multiple world populations, identifying susceptibility and resistance factors for diseases and in the impact of HLA mismatches in allogeneic transplantation; and 59 book chapters. He served as expert Consultant for Donor Searches for NMDP and as President Elect, President and Past President of the American Society for Histocompatibility and Immunogenetics. He served as a member of the Board of Directors and the Executive Committee for the United Network for Organ Sharing. He served as Co-Chair of the Immunobiology Committee of the CIBMTR; He also served as a member of the HHS Advisory Council on Blood Stem Cell Transplantation (ACBSCT).He serves as HLA Expert Consultant for the NMDP for the HRSA contract and is a member of the Histocompatibility Advisory Group for NMDP. He is Councilor of the International Histocompatibility Workshop and a member of the WHO Nomenclature Committee for Factors of the HLA System and was Chairman of the (17th) International HLA & Immunogenetics Workshop, and Past President of the International HLA & Immunogenetics Workshop.

Academic Appointments

• Professor - University Medical Line, Pathology

Contact

• Academic [email protected] University - Faculty Department: Pathology Clinical Position: Professor-Univ Med Line

• Administrative Contact Sonja Lewis-Rogers Administrative Assistant III [email protected]
  • 650-505-4812 (office)

Additional Info

• Mail Code: 5556
• ORCID: https://orcid.org/0000-0002-5707-2588

Links

• Curriculum Vitae DOC

2025-26 Courses

• Independent Studies (5)
  • Directed Reading in PathologyPATH 299 (Aut, Win, Spr, Sum)
  • Early Clinical Experience in PathologyPATH 280 (Aut, Win, Spr, Sum)
  • Graduate ResearchPATH 399 (Aut, Win, Spr, Sum)
  • Medical Scholars ResearchPATH 370 (Aut, Win, Spr, Sum)
  • Undergraduate ResearchPATH 199 (Aut, Win, Spr, Sum)

All Publications

• Replacements at Structural or Functional Dimorphisms 103, 109 and 167 Distinguish HLA Class I Serologically Defined Antigens. HLA Osoegawa, K., Son, J., Yim, K., Marsh, S. G., Fernández Viňa, M. A. 2025; 106 (3): e70387

  Abstract

  Amino acid variations in the HLA molecule may serve as part of serologic epitopes (residues determining epitopes: DEP) detected by allo-antibodies. In current clinical histocompatibility practices, the presence of anti-HLA donor-specific antibodies (DSA) is assessed by solid phase (SP) tests with single antigen bead (SAB) panels. The antigenic risk is assessed based on the mean fluorescence intensity (MFI) values corresponding to each SAB via virtual crossmatch (VXM). To improve the accuracy of the VXM, new Associated Antigens were proposed based on DEPs; however, the antigenicity of some DEPs remained uncertain. In the current study, highly complex reactive sera were selected, and the complexity was reduced by adsorption with magnetic beads or lymphocytes followed by acid/neutralisation processes. As a proof of concept, a patient's serum was enriched with SAB coated with HLA-A*01:01. The eluate was tested using SP-SAB and showed reactivity with the antigens HLA-A1, -A9 (excluding A2403), -A80, -B12 and -B76. This allowed for validation of the antibody enrichment process and identification of the serological equivalency of DEPs 167G and 167S shared by these antigens. We identified broadly reactive sera being positive with the SAB HLA-B*35:12 (103V) and negative with the other SAB HLA-B35 (103L). Allo-antibodies were enriched by the adsorption/elution procedure with lymphocytes expressing HLA-B*35:12 and with SABs coated with HLA-B*57:01. The SAB assay using one of the eluates showed an almost identical cross-reactivity pattern: positive with all HLA-B SABs bearing 103V and no reactivity with SABs bearing 103L, suggesting that the enriched antibodies reacted with epitope(s) shared by HLA-B*35:12 and HLA-B*57:01. Additional reactivity was detected with the SABs HLA-A32, -A74 and -Cw3. This allowed for identification of putative epitope(s) containing residues 103V and 109L. Another serum with positive reactivity to the SAB HLA-B*35:02 showed reactivity to almost all HLA-A SABs including -A*02:10 and was negative with other -A*02 and -A*69:01 SABs, suggesting that the involvement of 107G and 109F may define novel epitopes. These studies allowed us to propose 13 novel HLA-B Associated Antigens; DEPs 103 and 109 in HLA class I were fully included in HLA Allele To Serotype (HATS) software update that allowed for a more detailed serologic characterisation of all common HLA alleles in the world.

  View details for DOI 10.1111/tan.70387

  View details for PubMedID 40944463

• Allogeneic Hematopoietic Cell Donor Selection: Contemporary Guidelines from the NMDP/CIBMTR. Transplantation and cellular therapy Jimenez Jimenez, A. M., Spellman, S. R., Politikos, I., McCurdy, S. R., Devine, S. M., Malki, M. M., Bolon, Y. T., Lee, S. J., Dehn, J., Pidala, J., Maiers, M., Askar, M., Malmberg, C., Auletta, J. J., Stefanski, H., Broglie, L., Qayed, M., Horwitz, M., Wilder, J. S., Gooptu, M., Mehta, R. S., Fernandez-Viña, M., Shaw, B. E., Shaffer, B. C. 2025

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) remains a curative therapy for many patients with hematologic malignancies, bone marrow failure syndromes, inborn errors of immunity and metabolic disorders. Current donor selection strategies typically prioritize the selection of an HLA-matched donor over HLA mismatched ("alternative") donor sources, with a hierarchical approach to the donor search. More recent data challenge this rubric, particularly in the context of novel graft versus host disease (GVHD) prophylaxis strategies that demonstrate improved outcomes in alternative donor HCT recipients. In this setting, an increased emphasis on non-HLA factors (both donor characteristics and systemic factors) in determining donor selection is now feasible. In this guideline, we review recent evidence from prospective clinical trials as well as high-quality observational studies and provide expert panel recommendations on donor selection algorithms and prioritization in the era of novel GVHD prophylaxis. We then highlight important questions still to be answered in our field.

  View details for DOI 10.1016/j.jtct.2025.07.004

  View details for PubMedID 40619101

• Profiling the genetic diversity of the HLA system in Mexico using 9-locus allele and haplotype frequencies from donors in the NMDP Mexico donor center. Human immunology Madbouly, A., Bashyal, P., Banos, A., Ramirez, J., Whitaker, C., Fernandez-Vina, M., Springer, B., Ybarra, Y., Maiers, M., Bolon, Y. T. 2025; 86 (4): 111324

  Abstract

  Profiling the HLA diversity at the population level benefits multiple clinical and anthropological applications, such as tracing population migration, identifying genetic relationships between different groups, quantifying the added diversity in a global donor pool and matching for solid organ and stem cell transplantation. We calculated nine-locus HLA-A ∼ C ∼ B ∼ DRB1 ∼ DRB3/4/5 ∼ DQA1 ∼ DQB1 ∼ DPA1 ∼ DPB1 allele and haplotype frequencies in about 170,000 volunteer donor genotypes from the NMDP Mexico (NMDP MX, previously Be The Match Mexico) donor center. These donors are predominantly of Mexican ancestry recruited from multiple regions in Mexico. The goal of the study was to describe the HLA genetic profiles of the Mexican population and investigate the contribution of these donors' HLA in serving Mexican, US and international patients in need of hematopoietic cell transplants. Additionally, we estimated that almost all Mexican patients will have an available 5 of 8 or better matched donor in the NMDP MX donor center with matches also available for some of the Latino patients in the U.S. We demonstrate that Mexican populations clustered genetically and shared multiple frequent alleles and haplotypes with populations from the US Mexican or Chicano, US South/Central American Hispanic, and some Latino populations. Operationally, 78 % of NMDP Mexico donors contributed genotypes that were observed a total of three times or less on the registry, increasing the diversity of the overall NMDP registry. More than 300 donor collections were facilitated through the NMDP MX donor center serving mostly Hispanic/Latino patients in the US and abroad. This study highlights the importance of adding the NMDP MX donors to the worldwide donor pool and paves the way for a data-driven strategy for future planning and donor recruitment.

  View details for DOI 10.1016/j.humimm.2025.111324

  View details for PubMedID 40334347

• Replacements at Structural or Functional Dimorphisms 103, 109 and 167 Distinguish HLA Class I Serologically Defined Antigens Osoegawa, K., Son, J., Yim, K., Fernandez-Vina, M. A. WILEY. 2025

  View details for Web of Science ID 001525853600221

• The Allele A*68:26 Assigned to A-6801 SEROTYPE Does Not React With A68 Specific Sera of a Commercial Typing Kit-A Case Report Ulrich, S., Fernandez-Vina, M. A., Osoegawa, K., Posch, U. WILEY. 2025

  View details for Web of Science ID 001502685800255

• Replacements at Structural or Functional Dimorphisms 103, 109 and 167 Distinguish HLA Class I Serologically Defined Antigens Osoegawa, K., Son, J., Yim, K., Fernandez-Vina, M. A. WILEY. 2025

  View details for Web of Science ID 001502685800222

• The Allele A*68:26 Assigned to A-6801 SEROTYPE Does Not React With A68 Specific Sera of a Commercial Typing Kit-A Case Report Ulrich, S., Fernandez-Vina, M. A., Osoegawa, K., Posch, U. WILEY. 2025

  View details for Web of Science ID 001525853600243

• HLA allele and haplotype frequencies of eight Indian populations based on 130,518 registered stem cell donors. Frontiers in immunology Solloch, U. V., Kaniyath Madhusoodhanan, C., Lange, V., Sauter, J., Jagannathan, L., Paul, P., Fernández-Viña, M. A., Schmidt, A. H. 2025; 16: 1528177

  Abstract

  In hematopoietic stem cell transplantation, optimal results are achieved when donors and patients are matched regarding their human leukocyte antigen (HLA) genes. Population-specific HLA allele and haplotype frequency distributions determine the probabilities to find matched donors in a stem cell donor registry of given size and ethnic composition.To evaluate the needs of Indian patients with regard to future donor recruitment, we analyzed a large data set of n=130,518 potential stem cell donors registered with DKMS-BMST, a Bangalore-based donor registry with nationwide donor recruitment activities. We defined 8 subpopulations by native language and state of origin of both parents. The subpopulations comprised four samples belonging to the Dravidian language family (native language: Kannada/state of origin: Karnataka, Tamil/Tamil Nadu, Telugu/Andhra Pradesh and Malayalam/Kerala), and four samples belonging to the Indo-Aryan language group (Bengali/West Bengal, Gujarati/Gujarat, Hindi/Uttar Pradesh, Marathi/Maharashtra). The precise definition of subpopulations and large sample sizes between n=5,808 (Telugu/Andhra Pradesh) and n=14,866 (Malayalam/Kerala) are strengths of our study. Our results regarding HLA allele and haplotype frequencies refine published data.In terms of genetic relatedness, we observed a division of the subpopulations into a Southern and a Northwestern Indian cluster and the Bengali/West Bengal sample which differed significantly from the seven other subpopulations. Patients from Southern Indian populations are the main beneficiaries from the DKMS-BMST registry in the current ethnic composition. A more even nationwide coverage will be achieved in the future with the opening of local recruitment offices in different parts of India.

  View details for DOI 10.3389/fimmu.2025.1528177

  View details for PubMedID 40070842

  View details for PubMedCentralID PMC11893841

• Three Fields Allelic Haplotype Frequencies of HLA-DPA1 and-DPB1 Typed by Next Generation Sequencing of 563 Families in Chinese Han Population HLA Wang, J., He, J., Li, Z., Zhu, Y., Cao, D., Fu, H., Zhang, X., Fernandez-Vina, M. A., Rozemuller, E., Liu, X. 2024; 104 (6)

  View details for DOI 10.1111/tan.15810

  View details for Web of Science ID 001376593900001

• An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania. Cell Loh, L., Saunders, P. M., Faoro, C., Font-Porterias, N., Nemat-Gorgani, N., Harrison, G. F., Sadeeq, S., Hensen, L., Wong, S. C., Widjaja, J., Clemens, E. B., Zhu, S., Kichula, K. M., Tao, S., Zhu, F., Montero-Martin, G., Fernandez-Vina, M., Guethlein, L. A., Vivian, J. P., Davies, J., Mentzer, A. J., Oppenheimer, S. J., Pomat, W., Ioannidis, A. G., Barberena-Jonas, C., Moreno-Estrada, A., Miller, A., Parham, P., Rossjohn, J., Tong, S. Y., Kedzierska, K., Brooks, A. G., Norman, P. J. 2024

  Abstract

  Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A∗24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1∗114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1∗114+NK cells from First Nations Australian donors are inhibited through binding HLA-A∗24:02. The KIR3DL1∗114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.

  View details for DOI 10.1016/j.cell.2024.10.005

  View details for PubMedID 39476840

• A new strategy for systematically classifying HLA alleles into serological specificities: Update and refinement. HLA Osoegawa, K., Yim, K., Jeracki, M., Nguyen, T. N., Wang, L., Cho, A., David, R., Son, J., Mankey, A., Marsh, S. G., Gendzekhadze, K., Murphey, C., Fernández Viňa, M. A. 2024; 104 (4): e15702

  Abstract

  HLA antigens were historically defined according to the unique reactivity pattern of cells expressing HLA molecules with distinctive clusters of allo-antisera and/or monoclonal antibodies. Subsequently, amino acid residues determining epitopes (DEP) in the HLA molecule were correlated with reactivity patterns. In current clinical practice, the presence of allo-antibodies is assessed using Luminex-based solid phase single antigen bead (SAB) assays for transplantation. Recently, novel antigens were proposed for HLA molecules with DEP patterns that do not match any serologically defined antigens recognised by the WHO Nomenclature Committee. To validate the antigens, mean fluorescence intensity values of SABs tested on >13,000 patients' sera were extracted from clinical databases and analysed by scatter plots using a linear regression model. We found that when two proteins were considered as the same antigen in the original study, for example, HLA-A*02:01 and -A*02:06, their correlation ranked among the highest values at each locus. In contrast, discrete asymmetric outliers were observed when there were different antigens, for example, HLA-A*30:01 and -A*30:02, allowing validation and confirmation of 20 novel antigens for HLA-A, -B, -C and -DR. The outliers were confirmed to be true or false by flow cytometric crossmatches. In addition to the previously defined residues for antigen assignments, findings suggest that further distinction should be made for common antigens by including the substitutions at residue 67 of HLA-B, 67 and 74 of -DR. These serologic analyses can be applied systematically to identify and confirm novel antigens. These developments will lead to designing optimal SAB panels and further improving virtual donor-specific antibodies assessment.

  View details for DOI 10.1111/tan.15702

  View details for PubMedID 39435845

• ASTCT Consensus Recommendations on Testing and Treatment of Patients with Donor-specific Anti-HLA Antibodies. Transplantation and cellular therapy Kongtim, P., Vittayawacharin, P., Zou, J., Srour, S., Shaffer, B., Shapiro, R. M., Varma, A., McGuirk, J., Dholaria, B. R., McCurdy, S. R., DeZern, A. E., Bejanyan, N., Bashey, A., Furst, S., Castagna, L., Mariotti, J., Ruggeri, A., Bailen, R., Teshima, T., Xiao-Jun, H., Bonfim, C., Aung, F., Cao, K., Carpenter, P. A., Hamadani, M., Askar, M., Fernandez-Vina, M., Girnita, A., Ciurea, S. O. 2024

  Abstract

  Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients.

  View details for DOI 10.1016/j.jtct.2024.09.005

  View details for PubMedID 39260570

• Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses. The journal of allergy and clinical immunology. In practice Saper, V. E., Tian, L., Verstegen, R. H., Conrad, C. K., Cidon, M., Hopper, R. K., Kuo, C. S., Osoegawa, K., Baszis, K., Bingham, C. A., Ferguson, I., Hahn, T., Horne, A., Isupova, E. A., Jones, J. T., Kasapcopur, Ö., Klein-Gitelman, M. S., Kostik, M. M., Ozen, S., Phadke, O., Prahalad, S., Randell, R. L., Sener, S., Stingl, C., Abdul-Aziz, R., Akoghlanian, S., Al Julandani, D., Alvarez, M. B., Bader-Meunier, B., Balay-Dustrude, E. E., Balboni, I., Baxter, S. K., Berard, R. A., Bhattad, S., Bolaria, R., Boneparth, A., Cassidy, E. A., Co, D. O., Collins, K. P., Dancey, P., Dickinson, A. M., Edelheit, B. S., Espada, G., Flanagan, E. R., Imundo, L. F., Jindal, A. K., Kim, H. A., Klaus, G., Lake, C., Lapin, W. B., Lawson, E. F., Marmor, I., Mombourquette, J., Ogunjimi, B., Olveda, R., Ombrello, M. J., Onel, K., Poholek, C., Ramanan, A. V., Ravelli, A., Reinhardt, A., Robinson, A. D., Rouster-Stevens, K., Saad, N., Schneider, R., Selmanovic, V., Pasic, I. S., Shenoi, S., Shilo, N. R., Soep, J. B., Sura, A., Taber, S. F., Tesher, M., Tibaldi, J., Torok, K. S., Tsin, C. M., Vasquez-Canizares, N., Villacis Nunez, D. S., Way, E. E., Whitehead, B., Zemel, L. S., Sharma, S., Fernández-Viña, M. A., Mellins, E. D. 2024

  Abstract

  After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease.We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began.In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs.Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors.In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

  View details for DOI 10.1016/j.jaip.2024.07.002

  View details for PubMedID 39002722

• Curating Genetic Associations with Rheumatologic Autoimmune Diseases to Improve Patient Outcomes. Arthritis & rheumatology (Hoboken, N.J.) Bridges, S. L., Shapira, R., Aksentijevich, I., Mack, S. J., Merriman, T. R., Klein, C. J., Bowen, B. M., Klein, T. E. 2024

  View details for DOI 10.1002/art.42943

  View details for PubMedID 38965695

• The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection. Genome biology and evolution Hayeck, T. J., Li, Y., Mosbruger, T. L., Bradfield, J. P., Gleason, A. G., Damianos, G., Shaw, G. T., Duke, J. L., Conlin, L. K., Turner, T. N., Fernandez-Vina, M. A., Sarmady, M., Monos, D. S. 2024

  Abstract

  Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D, HKA, Dng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: 1) SNP genotyping and exome data, 2) targeted high-resolution HLA genotyping (IHIW), and 3) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions.

  View details for DOI 10.1093/gbe/evae009

  View details for PubMedID 38302106

• High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis. Frontiers in neurology Ma, Q., Augusto, D. G., Montero-Martin, G., Caillier, S. J., Osoegawa, K., Cree, B. A., Hauser, S. L., Didonna, A., Hollenbach, J. A., Norman, P. J., Fernandez-Vina, M., Oksenberg, J. R. 2023; 14: 1326738

  Abstract

  The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods.We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls.We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk.The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

  View details for DOI 10.3389/fneur.2023.1326738

  View details for PubMedID 38145128

  View details for PubMedCentralID PMC10739394

• Exceptional diversity of KIR and HLA class I in Egypt. HLA Montero-Martin, G., Kichula, K. M., Misra, M. K., de Brito Vargas, L., Marin, W. M., Hollenbach, J. A., Fernandez-Vina, M. A., Elfishawi, S., Norman, P. J. 2023

  Abstract

  Genetically determined variation of killer cell immunoglobulin like receptors (KIR) and their HLA class I ligands affects multiple aspects of human health. Their extreme diversity is generated through complex interplay of natural selection for pathogen resistance and reproductive health, combined with demographic structure and dispersal. Despite significant importance to multiple health conditions of differential effect across populations, the nature and extent of immunogenetic diversity is under-studied for many geographic regions. Here, we describe the first high-resolution analysis of KIR and HLA class I combinatorial diversity in Northern Africa. Analysis of 125 healthy unrelated individuals from Cairo in Egypt yielded 186 KIR alleles arranged in 146 distinct centromeric and 79 distinct telomeric haplotypes. The most frequent haplotypes observed were KIR-A, encoding two inhibitory receptors specific for HLA-C, two that are specific for HLA-A and -B, and no activating receptors. Together with 141 alleles of HLA class I, 75 of which encode a KIR ligand, we identified a mean of six distinct interacting pairs of inhibitory KIR and HLA allotypes per individual. We additionally characterize 16 KIR alleles newly identified in the study population. Our findings place Egyptians as one of the most highly diverse populations worldwide, with important implications for transplant matching and studies of immune-mediated diseases.

  View details for DOI 10.1111/tan.15177

  View details for PubMedID 37528739

• HLA allele and haplotype frequencies of registered stem cell donors in Chile. Frontiers in immunology Solloch, U. V., Giani, A. S., Pattillo Garnham, M. I., Sauter, J., Bernas, S. N., Lange, V., Barriga, F., Fernández-Viña, M. A., Schmidt, A. H. 2023; 14: 1175135

  Abstract

  Patients in need of hematopoietic stem cell transplantation often rely on unrelated stem cell donors matched in certain human leukocyte antigen (HLA) genes. Donor search is complicated by the extensive allelic variability of the HLA system. Therefore, large registries of potential donors are maintained in many countries worldwide. Population-specific HLA characteristics determine the registry benefits for patients and also the need for further regional donor recruitment. In this work, we analyzed HLA allele and haplotype frequencies of donors of DKMS Chile, the first Chilean donor registry, with self-assessed "non-Indigenous" (n=92,788) and "Mapuche" (n=1,993) ancestry. We identified HLA alleles that were distinctly more abundant in the Chilean subpopulations than in worldwide reference populations, four of them particularly characteristic for the Mapuche subpopulation, namely B*39:09g, B*35:09, DRB1*04:07g, and DRB1*16:02g. Both population subsamples carried haplotypes of both Native American and European origin at high frequencies, reflecting Chile's complex history of admixture and immigration. Matching probability analysis revealed limited benefits for Chilean patients (both non-Indigenous and Mapuche) from donor registries of non-Chilean donors, thus indicating a need for ongoing significant donor recruitment efforts in Chile.

  View details for DOI 10.3389/fimmu.2023.1175135

  View details for PubMedID 37313414

  View details for PubMedCentralID PMC10258311

• HLA-Bw4 is Associated with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Kizer, K., Augusto, D., Montero-Martin, G., Schlenk, N., Horgan, J., Wade, K., Oksenberg, J., Fernandez-Vina, M., Frankovich, J., Hollenbach, J. A. WILEY. 2023: 365

  View details for Web of Science ID 001082837700074

• HLA variants associated with sarcoidosis and their tag single nucleotide polymorphisms in Czechs Sikorova, K., Doubkova, M., Strnad, A., Kocourkova, L., Petrkova, J., Osoegawa, K., Fernandez-Vina, M. A., Petrek, M. WILEY. 2023: 372-373

  View details for Web of Science ID 001082837700089

• Spherotech-EDTA combined serum treatment reduces background more effectively as compared to One Lambda Adsorb Out™ and LIFECODES Serum Cleaner in Luminex-based solid-phase immunoassays for HLA antibody detection. HLA Misra, M. K., Weidner, J. G., Upchurch, R. L., Mankey, A. M., Fernandez-Viña, M. A., Marino, S. G. 2023

  Abstract

  Spherotech (SPT) microparticles capture non-specific binding materials present in test serum, and EDTA removes the so called" prozone effect". This study presents a novel approach of combined SPT-EDTA serum treatment prior to Luminex HLA antibody testing to remove high background, and prozone effect in a single step process, and compared the efficacy of SPT-EDTA serum pre-treatment with AdsorbOut (ADS) and Serum Cleaner (SC) to reduce background in solid phase immunoassays (SPI). A total of 21 serum samples with a history of elevated negative control (NC) values ≥500, and 20 samples with normal NC values were included to assess the potential adverse effects. A problem of high background was noted in 25% of our samples in SPI. We observed 80% effectiveness in reducing NC values 5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

  View details for DOI 10.1016/j.bbmt.2015.05.001

  View details for PubMedID 25985919

  View details for PubMedCentralID PMC4506716

• Are changes in HLA Ags responsible for leukemia relapse after HLA-matched allogeneic hematopoietic SCT? Bone marrow transplantation Hamdi, A., Cao, K., Poon, L. M., Aung, F., Kornblau, S., Fernandez Vina, M. A., Champlin, R. E., Ciurea, S. O. 2015; 50 (3): 411-413

  Abstract

  Loss of heterozygosity (LOH) has been shown to be associated with leukemia relapse after haploidentical transplantation. Whether such changes are an important cause of relapse after HLA-matched transplantation remains unclear. We retrospectively HLA-typed leukemic blasts for 71 patients with AML/myelodysplastic syndrome obtained from stored samples, and the results were compared with those obtained at diagnosis and/or before the transplant. No LOH or any other changes in HLA Ag were found in any of the samples tested post transplant as compared with pretransplant specimens. One patient had LOH in HLA class I Ag (HLA-A,-B and -C); however, these changes were present in the pretransplant sample indicating that they occurred before the transplant. We concluded that, in contrast with haploidentical transplantation, HLA loss does not have a major role as a mechanism of relapse after allogeneic transplantation with a closely HLA-matched donor.

  View details for DOI 10.1038/bmt.2014.285

  View details for PubMedID 25621795

• HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy. American journal of human genetics Ollila, H. M., Ravel, J., Han, F., Faraco, J., Lin, L., Zheng, X., Plazzi, G., Dauvilliers, Y., Pizza, F., Hong, S., Jennum, P., Knudsen, S., Kornum, B. R., Dong, X. S., Yan, H., Hong, H., Coquillard, C., Mahlios, J., Jolanki, O., Einen, M., Lavault, S., Högl, B., Frauscher, B., Crowe, C., Partinen, M., Huang, Y. S., Bourgin, P., Vaarala, O., Désautels, A., Montplaisir, J., Mack, S. J., Mindrinos, M., Fernandez-Vina, M., Mignot, E. 2015; 96 (1): 136-146

  Abstract

  Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

  View details for DOI 10.1016/j.ajhg.2014.12.010

  View details for PubMedID 25574827

  View details for PubMedCentralID PMC4289679

• Recommendations for Donor Human Leukocyte Antigen Assessment and Matching for Allogeneic Stem Cell Transplantation: Consensus Opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of blood and marrow transplantation Howard, C. A., Fernandez-Vina, M. A., Appelbaum, F. R., Confer, D. L., Devine, S. M., Horowitz, M. M., Mendizabal, A., Laport, G. G., Pasquini, M. C., Spellman, S. R. 2015; 21 (1): 4-7

  Abstract

  The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients with life-threatening disorders. Well-designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans, and graft source selection. In this perspective, we summarize evidence supporting criteria for the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. These standardized criteria for graft source selection have been adopted by the BMT CTN to enhance the interpretation of clinical findings within and among future clinical protocols.

  View details for DOI 10.1016/j.bbmt.2014.09.017

  View details for PubMedID 25278457

  View details for PubMedCentralID PMC4272893

• HLA-DQ Allele Competition in Narcolepsy: A Comment on Tafti et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe SLEEP Ollila, H. M., Fernandez-Vina, M., Mignot, E. 2015; 38 (1): 147-151

  Abstract

  Although HLA-DQB1*06:02 is the strongest predisposing genetic factor for narcolepsy, the effect of this gene must be considered alongside that of its polymorphic partner, DQA1. In this paper, we extend an analysis of the effect of HLA-DQB1 on narcolepsy risk published recently by Tafti et al.Imputing allelic variation at the level of HLA-DQA1, we show that this locus also has a considerable effect on disease susceptibility. Our data are also compatible with previous findings in multi-ethnic group data sets showing that allele competition effects within the DQ1 group determine the amount of DQ0602 (the DQA1*01:02/DQB1*06:02 heterodimer), and consequently, the risk of developing narcolepsy. We also found an independent predisposing effect of DQB1*03:01 via a currently unknown mechanism.Both DQA1 and DQB1 influence narcolepsy risk.

  View details for DOI 10.5665/sleep.4342

  View details for Web of Science ID 000347169300017

  View details for PubMedID 25325462

  View details for PubMedCentralID PMC4262948

• HLA allotype expressivity in transplantation BLOOD Fernandez-Vina, M. 2014; 124 (26): 3839–40

  View details for PubMedID 25525081

• HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/Orexin Deficiency SLEEP Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Vina, M. F., Mignot, E. 2014; 37 (10): 1601-1608

  Abstract

  To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

  View details for DOI 10.5665/sleep.4066

  View details for Web of Science ID 000343147400006

  View details for PubMedCentralID PMC4173917

• HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Fernandez Vina, M., Mignot, E. 2014; 37 (10): 1601-1608

  Abstract

  To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

  View details for DOI 10.5665/sleep.4066

  View details for PubMedID 25197808

• Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments TISSUE ANTIGENS Madbouly, A., Gragert, L., Freeman, J., Leahy, N., Gourraud, P., Hollenbach, J. A., Kamoun, M., Fernandez-Vina, M., Maiers, M. 2014; 84 (3): 285-292

  Abstract

  Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with average recall >76% when imputing HLA alleles from registry data. We simulated ambiguity generated by several HLA genotyping methods to evaluate the imputation performance on several levels of typing resolution. On average, imputation percent recall of allele-level HLA haplotypes was >95% for allele-level typing, >92% for intermediate resolution typing and >58% for serology (low-resolution) typing. Thus, allele-level HLA assignments can be imputed through the application of a set of statistical and population genetics inferences and with knowledge of haplotype frequencies and self-identified race and ethnicities.

  View details for DOI 10.1111/tan.12390

  View details for Web of Science ID 000341252500005

  View details for PubMedID 25040134

• Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1. Bone marrow transplantation Fleischhauer, K., Fernandez-Viña, M. A., Wang, T., Haagenson, M., Battiwalla, M., Baxter-Lowe, L. A., Ciceri, F., Dehn, J., Gajewski, J., Hale, G. A., Heemskerk, M. B., Marino, S. R., McCarthy, P. L., Miklos, D., Oudshoorn, M., Pollack, M. S., Reddy, V., Senitzer, D., Shaw, B. E., Waller, E. K., Lee, S. J., Spellman, S. R. 2014; 49 (9): 1176-1183

  Abstract

  HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.

  View details for DOI 10.1038/bmt.2014.122

  View details for PubMedID 24955785

• Cytotoxic T-lymphocyte antigen-4 single nucleotide polymorphisms are not associated with outcomes after unrelated donor transplantation: a center for international blood and marrow transplant research analysis. Biology of blood and marrow transplantation Sengsayadeth, S., Wang, T., Lee, S. J., Haagenson, M. D., Spellman, S., Fernandez Viña, M. A., Muller, C. R., Verneris, M. R., Savani, B. N., Jagasia, M. 2014; 20 (6): 900-903

  Abstract

  Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.

  View details for DOI 10.1016/j.bbmt.2014.03.005

  View details for PubMedID 24631737

• Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood Fernandez-Viña, M. A., Wang, T., Lee, S. J., Haagenson, M., Aljurf, M., Askar, M., Battiwalla, M., Baxter-Lowe, L., Gajewski, J., Jakubowski, A. A., Marino, S., Oudshoorn, M., Marsh, S. G., Petersdorf, E. W., Schultz, K., Turner, E. V., Waller, E. K., Woolfrey, A., Umejiego, J., Spellman, S. R., Setterholm, M. 2014; 123 (8): 1270-1278

  Abstract

  In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.

  View details for DOI 10.1182/blood-2013-10-532671

  View details for PubMedID 24408320

  View details for PubMedCentralID PMC3931192

• Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy BLOOD Eapen, M., Klein, J. P., Ruggeri, A., Spellman, S., Lee, S. J., Anasetti, C., Arcese, W., Barker, J. N., Baxter-Lowe, L. A., Brown, M., Fernandez-Vina, M. A., Freeman, J., He, W., Iori, A. P., Horowitz, M. M., Locatelli, F., Marino, S., Maiers, M., Michel, G., Sanz, G. F., Gluckman, E., Rocha, V. 2014; 123 (1): 133-140

  Abstract

  We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units.

  View details for DOI 10.1182/blood-2013-05-506253

  View details for Web of Science ID 000329742300024

  View details for PubMedID 24141369

  View details for PubMedCentralID PMC3879902

• Dual Cases of Type 1 Narcolepsy with Schizophrenia and Other Psychotic Disorders JOURNAL OF CLINICAL SLEEP MEDICINE Canellas, F., Lin, L., Rosa Julia, M., Clemente, A., Vives-Bauza, C., Ollila, H. M., Hong, S. C., Arboleya, S. M., Einen, M. A., Faraco, J., Fernandez-Vina, M., Mignot, E. 2014; 10 (9): 1011-1018

  Abstract

  Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia.Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens.Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable.Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted.

  View details for DOI 10.5664/jcsm.4040

  View details for Web of Science ID 000341999700012

  View details for PubMedID 25142772

  View details for PubMedCentralID PMC4153110

• Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality BLOOD Pidala, J., Wang, T., Haagenson, M., Spellman, S. R., Askar, M., Battiwalla, M., Baxter-Lowe, L. A., Bitan, M., Fernandez-Vina, M., Gandhi, M., Jakubowski, A. A., Maiers, M., Marino, S. R., Marsh, S. G., Oudshoorn, M., Palmer, J., Prasad, V. K., Reddy, V., Ringden, O., Saber, W., Santarone, S., Schultz, K. R., Setterholm, M., Trachtenberg, E., Turner, E. V., Woolfrey, A. E., Lee, S. J., Anasetti, C. 2013; 122 (22): 3651-3658

  Abstract

  HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death.

  View details for DOI 10.1182/blood-2013-05-501510

  View details for Web of Science ID 000329726200021

  View details for PubMedID 23982174

  View details for PubMedCentralID PMC3837514

• HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations PLOS ONE Zuniga, J., Yu, N., Barquera, R., Alosco, S., Ohashi, M., Lebedeva, T., Acuna-Alonzo, V., Yunis, M., Granados-Montiel, J., Cruz-Lagunas, A., Vargas-Alarcon, G., Rodriguez-Reyna, T. S., Fernandez-Vina, M., Granados, J., Yunis, E. J. 2013; 8 (9)

  Abstract

  Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/-B and -DRB1/-DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations.

  View details for DOI 10.1371/journal.pone.0074442

  View details for Web of Science ID 000326520200031

  View details for PubMedID 24086347

  View details for PubMedCentralID PMC3781075

• Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood Fernández-Viña, M. A., Klein, J. P., Haagenson, M., Spellman, S. R., Anasetti, C., Noreen, H., Baxter-Lowe, L. A., Cano, P., Flomenberg, N., Confer, D. L., Horowitz, M. M., Oudshoorn, M., Petersdorf, E. W., Setterholm, M., Champlin, R., Lee, S. J., de Lima, M. 2013; 121 (22): 4603-4610

  Abstract

  A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.

  View details for DOI 10.1182/blood-2013-02-481945

  View details for PubMedID 23596045

  View details for PubMedCentralID PMC3668493

• Birth Order and Transplantation Outcome in HLA-Identical Sibling Stem Cell Transplantation: An Analysis on Behalf of the Center for International Blood and Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dobbelstein, C., Ahn, K. W., Haagenson, M., Hale, G. A., Van Rood, J. J., Miklos, D., Waller, E. K., Spellman, S. R., Fernandez-Vina, M., Ganser, A., Aljurf, M., Bornhaeuser, M., Gupta, V., Marino, S. R., Pollack, M. S., Reddy, V., Eder, M., Lee, S. J. 2013; 19 (5): 741-745

  Abstract

  Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.

  View details for DOI 10.1016/j.bbmt.2013.01.020

  View details for Web of Science ID 000318132500010

  View details for PubMedID 23380341

• Common and well-documented HLA alleles: 2012 update to the CWD catalogue TISSUE ANTIGENS Mack, S. J., Cano, P., Hollenbach, J. A., He, J., Hurley, C. K., Middleton, D., Moraes, M. E., Pereira, S. E., Kempenich, J. H., Reed, E. F., Setterholm, M., Smith, A. G., Tilanus, M. G., Torres, M., Varney, M. D., Voorter, C. E., Fischer, G. F., Fleischhauer, K., Goodridge, D., Klitz, W., Little, A., Maiers, M., Marsh, S. G., Mueller, C. R., Noreen, H., Rozemuller, E. H., Sanchez-Mazas, A., Senitzer, D., Trachtenberg, E., Fernandez-Vina, M. 2013; 81 (4): 194-203

  Abstract

  We have updated the catalogue of common and well-documented (CWD) human leukocyte antigen (HLA) alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci in IMGT (IMmunoGeneTics)/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being 'common' (having known frequencies) and 707 as being 'well-documented' on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program's bioinformatics web pages.

  View details for DOI 10.1111/tan.12093

  View details for Web of Science ID 000316628100002

  View details for PubMedID 23510415

  View details for PubMedCentralID PMC3634360

• 16th IHIW: Global distribution of extended HLA haplotypes INTERNATIONAL JOURNAL OF IMMUNOGENETICS Askar, M., Daghstani, J., Thomas, D., Leahy, N., Dunn, P., Claas, F., Doran, S., Saji, H., Kanangat, S., Karoichane, M., Tambur, A., Monos, D., El-Khalifa, M., Turner, V., Kamoun, M., Mustafa, M., Ramon, D., Gandhi, M., Vernaza, A., Gorodezky, C., Wagenknecht, D., Gautreaux, M., Hajeer, A., Kashi, Z., Fernandez-Vina, M. 2013; 40 (1): 31-38

  Abstract

  This report describes the project to identify the global distribution of extended HLA haplotypes, a component of 16th International HLA and Immunogenetics Workshop (IHIW), and summarizes the initial analyses of data collected. The project aims to investigate extended HLA haplotypes, compare their distribution among different populations, assess their frequency in hematopoietic stem cell unrelated donor registries and initiate an international family studies database and DNA repository to be made publicly available. HLA haplotypes compiled in immunogenetics laboratories during the evaluation of transplant candidates and related potential donors were analysed. Haplotypes were determined using the pedigree analysis tool publicly available from the National Marrow Donor Program (NMDP) website. Nineteen laboratories from 10 countries (11 laboratories from North America, five from Asia, two from Latin America and one from Australia) contributed data on a total of 1719 families comprised of 7474 individuals. We identified 10393 HLA haplotypes, of which 1682 haplotypes included high-resolution typing at HLA-A, B, C, DRB1 and DQB1 loci. We also present haplotypes containing MICA and other HLA loci and haplotypes containing rare alleles seen in these families. The project will be extended through the 17th IHIW, and investigators interested in joining the project may communicate with the first author.

  View details for DOI 10.1111/iji.12029

  View details for Web of Science ID 000313488000006

  View details for PubMedID 23302097

• 16th IHIW: Extending the number of resources and bioinformatics analysis for the investigation of HLA rare alleles INTERNATIONAL JOURNAL OF IMMUNOGENETICS Gonzalez-Galarza, F. F., Mack, S. J., Hollenbach, J., Fernandez-Vina, M., Setterholm, M., Kempenich, J., Marsh, S. G., Jones, A. R., Middleton, D. 2013; 40 (1): 60-65

  Abstract

  Continuing a project presented at the 15th International HLA and Immunogenetics Workshop (IHIWS) on the rarity of HLA alleles, we sought to expand the number of data sources and bioinformatics tools available in the Allele Frequencies Net Database website (AFND, www.allelefrequencies.net). In this 16th IHIWS Rare Alleles project, HLA alleles described in the latest IMGT/HLA Database (release 3.8.0) were queried against different sources including data from registries (stem cell) and from 74 different laboratories around the world. We demonstrated that approximately 40% of the alleles officially named in the IMGT/HLA Database have been reported only once across all different sources. To facilitate the large-scale analysis of rare alleles, we have produced an online tool called the Rare Allele Detector that simplifies the detection of alleles that are considered to be 'very rare', 'rare' or 'frequent'. Tools and associated data can be accessed via the www.allelefrequencies.net website.

  View details for DOI 10.1111/iji.12030

  View details for Web of Science ID 000313488000010

  View details for PubMedID 23198982

• New approaches in alternative donor transplantation. Biology of blood and marrow transplantation Fernandez Vina, M., Heslop, H. E., Barker, J. N. 2013; 19 (1): S91-6

  View details for DOI 10.1016/j.bbmt.2012.10.027

  View details for PubMedID 23110984

• New Approaches in Alternative Donor Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Vina, M. F., Heslop, H. E., Barker, J. N. 2013; 19 (1): S91-S96

  View details for DOI 10.1016/j.bbmt.2012.10.027

  View details for Web of Science ID 000313998100023

• Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Ciurea, S. O., Mulanovich, V., Saliba, R. M., Bayraktar, U. D., Jiang, Y., Bassett, R., Wang, S. A., Konopleva, M., Fernandez-Vina, M., Montes, N., Bosque, D., Chen, J., Rondon, G., Alatrash, G., Alousi, A., Bashir, Q., Korbling, M., Qazilbash, M., Parmar, S., Shpall, E., Nieto, Y., Hosing, C., Kebriaei, P., Khouri, I., Popat, U., de Lima, M., Champlin, R. E. 2012; 18 (12): 1835-1844

  Abstract

  Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

  View details for DOI 10.1016/j.bbmt.2012.07.003

  View details for Web of Science ID 000311593900010

  View details for PubMedID 22796535

• HLA factors in transplantation for nonmalignant hematologic disorders BLOOD Fernandez-Vina, M. A. 2012; 120 (14): 2781-2782

  Abstract

  In this issue of Blood, a study by Horan and colleagues shows that differences in the HLA alleles of patients and unrelated donors in hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases result in increased risk for adverse treatment outcome.(1) This is the largest dataset examined so far for the evaluation of HLA mismatches in HSCT for nonmalignant diseases. It includes predominantly pediatric patients diagnosed with 39 diseases. Many patients received nonmyeloablative conditioning; a significant proportion of the infused grafts were depleted of T-lymphocytes; 6 diseases account for 77% of the cases.

  View details for DOI 10.1182/blood-2012-08-446567

  View details for Web of Science ID 000311616900007

  View details for PubMedID 23043027

• A combined DPA1 similar to DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer IMMUNOGENETICS Hollenbach, J. A., Madbouly, A., Gragert, L., Vierra-Green, C., Flesch, S., Spellman, S., Begovich, A., Noreen, H., Trachtenberg, E., Williams, T., Yu, N., Shaw, B., Fleischhauer, K., Fernandez-Vina, M., Maiers, M. 2012; 64 (8): 559-569

  Abstract

  Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context.

  View details for DOI 10.1007/s00251-012-0615-3

  View details for Web of Science ID 000306341300001

  View details for PubMedID 22526601

  View details for PubMedCentralID PMC3395342

• High-throughput, high-fidelity HLA genotyping with deep sequencing PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wang, C., Krishnakumar, S., Wilhelmy, J., Babrzadeh, F., Stepanyan, L., Su, L. F., Levinson, D., Fernandez-Vina, M. A., Davis, R. W., Davis, M. M., Mindrinos, M. 2012; 109 (22): 8676-8681

  Abstract

  Human leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especially autoimmunity and infectious diseases. Despite their importance, however, they are rarely characterized comprehensively because of the prohibitive cost of standard technologies and the technical challenges of accurately discriminating between these highly related genes and their many allelles. Here we demonstrate a high-resolution, and cost-effective methodology to type HLA genes by sequencing, which combines the advantage of long-range amplification, the power of high-throughput sequencing platforms, and a unique genotyping algorithm. We calibrated our method for HLA-A, -B, -C, and -DRB1 genes with both reference cell lines and clinical samples and identified several previously undescribed alleles with mismatches, insertions, and deletions. We have further demonstrated the utility of this method in a clinical setting by typing five clinical samples in an Illumina MiSeq instrument with a 5-d turnaround. Overall, this technology has the capacity to deliver low-cost, high-throughput, and accurate HLA typing by multiplexing thousands of samples in a single sequencing run, which will enable comprehensive disease-association studies with large cohorts. Furthermore, this approach can also be extended to include other polymorphic genes.

  View details for DOI 10.1073/pnas.1206614109

  View details for PubMedID 22589303

• Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Vina, M., Hollenbach, J. A., Lyke, K. E., Sztein, M. B., Maiers, M., Klitz, W., Cano, P., Mack, S., Single, R., Brautbar, C., Israel, S., Raimondi, E., Khoriaty, E., Inati, A., Andreani, M., Testi, M., Moraes, M., Thomson, G., Stastny, P., Cao, K. 2012; 367 (1590): 820–29

  Abstract

  The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.

  View details for PubMedID 22312049

• Frequency of HLA-DP-specific antibodies and a possible new cross-reacting group HUMAN IMMUNOLOGY Callender, C. J., Fernandez-Vina, M., Leffell, M. S., Zachary, A. A. 2012; 73 (2): 175-179

  Abstract

  Clinical studies have demonstrated that HLA-DP-specific antibodies can be detrimental to a transplanted kidney. The number of patients affected is proportional to the frequency of DP antibodies. We determined the frequency of HLA-DP-specific antibodies en toto and in the absence of cross-reactive DR antibodies. Of 650 waitlisted renal patients, 271 (42%) were reactive with HLA-DP antigens in solid-phase immunoassays. Of these 271 sera, 58 (21%) were negative for reactivity with cross-reactive DR antigens, and 16 (5.9%) had no class II antibody other than DP. Eliminating sera containing DR cross-reactive antibodies reduced the frequency but not the overall strength of DP antibodies. Although most DP antibodies were not expected to yield a positive cytotoxicity crossmatch, 2 DP-specific antibodies yielded cytotoxic crossmatch tests with titers of >512. The occurrence of HLA-DP-specific antibody differed significantly between previously transplanted (62%) and nontransplanted (38%) patients, but no difference was observed among patients categorized by race or sex. One serum demonstrated strong cross-reactivity between DP and DRB1*01:03 in the absence of DR1 or DR11 reactivity. Sequence alignments were performed and a possible new cross-reactivity between DRB1*01:03 and DP2, DP9, DP10, DP13, DP16, and DP17 was defined. Two additional sera confirmed this cross-reactivity.

  View details for DOI 10.1016/j.humimm.2011.11.006

  View details for Web of Science ID 000300123200006

  View details for PubMedID 22138757

• Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease PLOS GENETICS Chen, H., Hayashi, G., Lai, O. Y., Dilthey, A., Kuebler, P. J., Wong, T. V., Martin, M. P., Vina, M. A., McVean, G., Wabl, M., Leslie, K. S., Maurer, T., Martin, J. N., Deeks, S. G., Carrington, M., Bowcock, A. M., Nixon, D. F., Liao, W. 2012; 8 (2)

  Abstract

  An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis.

  View details for DOI 10.1371/journal.pgen.1002514

  View details for Web of Science ID 000300725500032

  View details for PubMedID 22577363

  View details for PubMedCentralID PMC3343879

• Humoral HLA sensitization matters in CBT outcome BLOOD Fernandez-Vina, M. A., de Lima, M., Ciurea, S. O. 2011; 118 (25): 6482-6484

  Abstract

  In this issue of Blood, Cutler and colleagues present evidence that donor-specific anti-HLA antibodies are associated with graft failure in double umbilical cord blood transplantation (CBT).1 Engraftment of donor cells is the first important step in successful transplantation and, until recently, the causes of engraftment failure remained elusive.

  View details for Web of Science ID 000298157600008

  View details for PubMedID 22174308

• The Outcomes of Family Haploidentical Hematopoietic Stem Cell Transplantation in Hematologic Malignancies Are Not Associated with Patient Age BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dong, L., Wu, T., Gao, Z., Zhang, M., Kan, F., Spellman, S. R., Tan, X., Zhao, Y., Wang, J., Lu, D., Miklos, D., Petersdorf, E., Fernandez-Vina, M., Lee, S. J. 2011; 17 (8): 1205-1213

  Abstract

  Haploidentical hematopoietic cell transplantation (HCT) has been used to treat hematologic malignancies, but it is unknown whether the procedure is more effective in adults or children. To address this question, we analyzed patients aged 1 to 65 years old receiving myeloablative conditioning regimens followed by family 2 to 3 antigen HLA-mismatched HCT and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR; n = 137) or performed in Dao-Pei Hospital in China, China (n = 181). The Dao-Pei cohort had more acute and chronic graft-versus-host disease (GVHD), less relapse, lower transplant-related mortality (TRM), and better leukemia-free survival (LFS) than the CIBMTR cohort. Overall survival (OS) and outcomes were similar between adults and children. In the CIBMTR cohort receiving ex vivo T cell depletion (TCD), adults had higher TRM (relative risk [RR] 2.71, 95% confidence interval [CI] 1.29-5.69, P = .008) and lower OS (RR 1.75, 95% CI 1.08-2.84, P = .023) than children. In the CIBMTR subset that did not receive ex vivo TCD, relapse was lower in adults compared to children (RR 0.24, 95% CI 0.07-0.80, P = .020), but TRM, LFS, and OS were similar. We conclude that outcomes in adults and children are similar overall, although children have better survival than adults if ex vivo TCD is used.

  View details for DOI 10.1016/j.bbmt.2010.12.703

  View details for Web of Science ID 000293429600013

  View details for PubMedID 21193055

  View details for PubMedCentralID PMC3113644

• Immunogenetics as a tool in anthropological studies IMMUNOLOGY Sanchez-Mazas, A., Fernandez-Vina, M., Middleton, D., Hollenbach, J. A., Buhler, S., Di, D., Rajalingam, R., Dugoujon, J., Mack, S. J., Thorsby, E. 2011; 133 (2): 143-164

  Abstract

  The genes coding for the main molecules involved in the human immune system--immunoglobulins, human leucocyte antigen (HLA) molecules and killer-cell immunoglobulin-like receptors (KIR)--exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. 'Genetic marker' (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen-binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host-pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different--either stochastic or deterministic--forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies.

  View details for DOI 10.1111/j.1365-2567.2011.03438.x

  View details for Web of Science ID 000289832100001

  View details for PubMedID 21480890

  View details for PubMedCentralID PMC3088978

• An update to HLA Nomenclature, 2010 BONE MARROW TRANSPLANTATION Marsh, S. G., Albert, E. D., Bodmer, W. F., Bontrop, R. E., DuPont, B., Erlich, H. A., Fernandez-Vina, M., Geraghty, D. E., Holdsworth, R., Hurley, C. K., Lau, M., Lee, K. W., Mach, B., Maiers, M., Mayr, W. R., Mueller, C. R., Parham, P., Petersdorf, E. W., Sasazuki, T., STROMINGER, J. L., Svejgaard, A., Terasaki, P. I., Tiercy, J. M., Trowsdale, J. 2010; 45 (5): 846-848

  Abstract

  The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports.

  View details for DOI 10.1038/bmt.2010.79

  View details for Web of Science ID 000277596700008

  View details for PubMedID 20348972

• Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups AMERICAN JOURNAL OF HUMAN GENETICS Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X. H., Lin, X. Y., Okun, M., Hohjoh, H., Miki, T., Hsu, S. H., Leffell, M. S., GRUMET, F. C., Fernandez-Vina, M., Honda, M., Risch, N. 2001; 68 (3): 686-699

  Abstract

  Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

  View details for Web of Science ID 000166994200013

  View details for PubMedID 11179016

• Complement-Binding Donor-Specific Anti-HLA Antibodies: Biomarker for Immunologic Risk Stratification in Pediatric Kidney Transplantation Recipients Transpl Int, Sigurjonsdottir, V. K. 2022; 35

  View details for DOI 10.3389/ti.2021.10158

• Delayed Kinetics of IgG, but not IgA, Anti-spike Antibodies in Transplant Recipients following SARS-CoV-2 Infection. J Am Soc Nephrol. Cravedi, P. 2021

  View details for DOI 10.1681/ASN.2021040573

• Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease. Journal of immunology (Baltimore, Md. : 1950) Anderson, K. M., Augusto, D. G., Dandekar, R., Shams, H., Zhao, C., Yusufali, T., Montero-Martin, G., Marin, W. M., Nemat-Gorgani, N., Creary, L. E., Caillier, S., Mofrad, M. R., Parham, P., Fernandez-Vina, M., Oksenberg, J. R., Norman, P. J., Hollenbach, J. A. 2020

  Abstract

  Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.

  View details for DOI 10.4049/jimmunol.2000144

  View details for PubMedID 32709660

• The Killer Immunoglobulin-like Receptor KIR3DL1 in Combination with HLA-Bw4 Is Associated with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Frankovich, J., Anderson, K., Montero-Martin, G., Chan, A., Thienemann, M., Farhadian, B., Willett, T., Mellins, E., Madden, A., Murphy, T., Swedo, S., Fernandez-Vina, M., Hollenbach, J. WILEY. 2020: 255–57

  View details for Web of Science ID 000542687800146

• Preface: 17th International HLA and Immunogenetics Workshop. Human immunology Vayntrub, T. A., Mack, S. J., Fernandez-Vina, M. A. 2020

  View details for DOI 10.1016/j.humimm.2020.01.008

  View details for PubMedID 32051104

• Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorder. JCI insight Maloney, E. M., Busque, V. A., Hui, S. T., Toh, J. n., Fernandez-Vina, M. n., Krams, S. M., Esquivel, C. O., Martinez, O. M. 2020; 5 (6)

  Abstract

  Epstein-Barr Virus (EBV) is a ubiquitous virus linked to a variety of lymphoid and epithelial malignancies. In solid organ and hematopoietic stem cell transplant recipients, EBV is causally associated with posttransplant lymphoproliferative disorder (PTLD), a group of heterogeneous lymphoid diseases. EBV+ B cell lymphomas that develop in the context of PTLD are generally attributed to the immunosuppression required to promote graft survival, but little is known regarding the role of EBV genome diversity in the development of malignancy. We deep-sequenced the EBV genome from the peripheral blood of 18 solid organ transplant recipients, including 6 PTLD patients. Sequences from 6 EBV+ spontaneous lymphoblastoid B cell lines (SLCL) were similarly analyzed. The EBV genome from PTLD patients had a significantly greater number of variations than EBV from transplant recipients without PTLD. Importantly, there were 15 nonsynonymous variations, including 8 in the latent cycle gene EBNA3C that were associated with the development of PTLD. One of the nonsynonymous variations in EBNA3C is located within a previously defined T cell epitope. These findings suggest that variations in the EBV genome can contribute to the pathogenesis of PTLD.

  View details for DOI 10.1172/jci.insight.131644

  View details for PubMedID 32213705

• A NOVEL FLOW CYTOMETRY CROSSMATCH FOR DETECTING TRUE DP-DSA INTERACTING TO THE NATIVE DP MOLECULES ON CELL SURFACE < DP-FXM > Wang, L., Fernandez-Vina, M., Chen, G. ELSEVIER SCIENCE INC. 2019: 126–27

  View details for DOI 10.1016/j.humimm.2019.07.153

  View details for Web of Science ID 000489085600150

• GENERATION AND CHARACTERIZATION OF HUMANIZED ANTI-HLA-A2 ANTIBODY Rodriguez-Paris, J. M., Wang, L., Lin, L., Fernandez-Vina, M., Chen, G. ELSEVIER SCIENCE INC. 2019: 109

  View details for DOI 10.1016/j.humimm.2019.07.130

  View details for Web of Science ID 000489085600127

• HLA-DP PROTEIN EXPRESSION LEVEL AND ITS IMPACT ON FLOW CYTOMETRY CROSSMATCH (FXM) Wang, L., Chen, G., Fernandez-Vina, M. ELSEVIER SCIENCE INC. 2019: 9–10

  View details for DOI 10.1016/j.humimm.2019.07.005

  View details for Web of Science ID 000489085600004

• Urgent Time to Allogeneic Hematopoietic Cell Transplantation: A National Survey of Transplant Physicians and Unrelated Donor Search Coordinators Facilitated by the Histocompatibility Advisory Group to the National Marrow Donor Program. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Pidala, J., Mupfudze, T. G., Payton, T., Barker, J., Perales, M., Shaw, B. E., Fernandez-Vina, M., Burns, L. J., Dehn, J. 2019

  Abstract

  PURPOSE: To characterize donor search and selection practices, the National Marrow Donor Program (NMDP) Histocompatibility Advisory Group developed a survey of allogeneic hematopoietic cell transplant (HCT) physicians and search coordinators. Objectives were to describe search practices, understand practices surrounding urgent time to HCT, and characterize strategies used when identifying a matched unrelated donor (MUD) is unlikely.METHODS: Participants included United States physician members of the American Society for Transplantation and Cellular Therapy (ASTCT) and donor search coordinators within the NMDP network. The web-based survey was conducted February to May 2018.RESULTS: A total of 317/858 physicians (37%) and 225/327 coordinators (69%) responded, of which 263 and 194 respectively were eligible and were included in the analysis. Most centers, 142 (95%) were represented; 108 (72%) had at least one physician and 128 (85%) had at least one coordinator respondent. Most (68% physicians, 61% coordinators) indicated donor selection decisions were made by individual physicians. Urgent time to HCT was most commonly (90 and 87%, of physicians and coordinators, respectively) defined as HCT within 4-6 weeks of search initiation. Higher HCT urgency was associated with a higher disease risk index. For urgent cases with low probability of an 8/8 MUD, 75 and 80% of physicians and coordinators endorsed short (1-2 weeks) unrelated donor search before proceeding to an alternative donor source. NMDP-provided solutions to expedite donor identification were strongly endorsed.CONCLUSIONS: This survey clarified current donor selection practices in the United States and defined urgent time to HCT. These data provide insight to NMDP on potential solutions to support the path to transplant, such as highlighting futile searches and providing alternative donor options at the time of search initiation.

  View details for DOI 10.1016/j.bbmt.2019.08.002

  View details for PubMedID 31419569

• 17th IHIW component "Immunogenetics of Ageing" - New NGS data. Human immunology Ivanova, M., Creary, L. E., Al Hadra, B., Lukanov, T., Mazzocco, M., Sacchi, N., Ameen, R., Al-Shemmari, S., Moise, A., Ursu, L. D., Constantinescu, I., Vayntrub, T., Fernandez-Vina, M. A., Shivarov, V., Naumova, E. 2019

  Abstract

  The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1, HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing.

  View details for DOI 10.1016/j.humimm.2019.07.287

  View details for PubMedID 31331679

• Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-lymphoblastoid cell lines: Report from the 17th International HLA and Immunogenetics Workshop Creary, L. E., Guerra, S. G., Chong, W., Brown, C. J., Turner, T. R., Robinson, J., Bultitude, W. P., Mayor, N. P., Marsh, S. G. E., Saito, K., Lam, K., Duke, J. L., Mosbruger, T. L., Ferriola, D., Monos, D., Willis, A., Askar, M., Fischer, G., Saw, C., Ragoussis, J., Petrek, M., Serra-Pages, C., Juan, M., Stavropoulos-Giokas, C., Dinou, A., Ameen, R., Al Shemmari, S., Spierings, E., Gendzekhadze, K., Morris, G. P., Zhang, Q., Kashi, Z., Hsu, S., Gangavarapu, S., Mallempati, K. C., Yamamoto, F., Osoegawa, K., Vayntrub, T., Chang, C., Hansen, J. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 449–60

  View details for DOI 10.1016/j.humimm.2019.03.001

  View details for Web of Science ID 000474324200013

• High-resolution characterization of allelic and haplotypic HLA frequency distribution in a Spanish population using high-throughput next-generation sequencing Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Sanchez-Gordo, F., Herrero-Mata, M. J., Balas, A., Vicario, J. L., Sanchez-Garcia, F., Gonzalez-Escribano, M. F., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Ocejo-Vinyals, J. G., Marin, L., Creary, L. E., Osoegawa, K., Vayntrub, T., Caro-Oleas, J. L., Vilches, C., Planelles, D., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 429–36

  View details for DOI 10.1016/j.humimm.2019.02.005

  View details for Web of Science ID 000474324200011

• Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes Barsakis, K., Babrzadeh, F., Chi, A., Mallempati, K., Pickle, W., Mindrinos, M., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 437–48

  View details for DOI 10.1016/j.humimm.2019.04.001

  View details for Web of Science ID 000474324200012

• Role of killer cell immunoglobulin-like receptor (KIR)-ligand interactions to prevent relapse in patients (pts) receiving matched unrelated stem cell transplant (SCT) for acute myeloid leukemia (AML). Rafei, H., Fernandez-Vina, M., Carmazzi, Y., Moore, B., Willis, D., Basar, R., Banerjee, P., Daher, M., Hosing, C., Kebriaei, P., Khouri, I. F., Mehta, R., Nieto, Y., Qazilbash, M. H., Shpall, E. J., Champlin, R. E., Marin, D., Rezvani, K., Cao, K. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806250

• Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes. Human immunology Barsakis, K., Babrzadeh, F., Chi, A., Mallempati, K., Pickle, W., Mindrinos, M., Fernandez-Vina, M. A. 2019

  Abstract

  Next Generation Sequencing allows for testing and typing of entire genes of the HLA region. A better and comprehensive sequence assessment can be achieved by the inclusion of full gene sequences of all the common alleles at a given locus. The common alleles of DRB5 are under-characterized with the full exon-intron sequence of two alleles available. In the present study the DRB5 genes from 18 subjects alleles were cloned and sequenced; haplotype analysis showed that 17 of them had a single copy of DRB5 and one consanguineous subject was homozygous at all HLA loci. Methodological approaches including robust and efficient long-range PCR amplification, molecular cloning, nucleotide sequencing and de novo sequence assembly were combined to characterize DRB5 alleles. DRB5 sequences covering from 5'UTR to the end of intron 5 were obtained for DRB5*01:01, 01:02 and 02:02; partial coverage including a segment spanning exon 2 to exon 6 was obtained for DRB5*01:03, 01:08N and 02:03. Phylogenetic analysis of the generated sequences showed that the DRB5 alleles group together and have distinctive differences with other DRB loci. Novel intron variants of DRB5*01:01:01, 01:02 and 02:02 were identified. The newly characterized DRB5 intron variants of each DRB5 allele were found in subjects harboring distinct associations with alleles of DRB1, B and/or ethnicity. The new information provided by this study provides reference sequences for HLA typing methodologies. Extending sequence coverage may lead to identify the disease susceptibility factors of DRB5 containing haplotypes while the unexpected intron variations may shed light on understanding of the evolution of the DRB region.

  View details for PubMedID 30954494

• High-resolution characterization of allelic and haplotypic HLA frequency distribution in a Spanish population using high-throughput next-generation sequencing. Human immunology Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Sanchez-Gordo, F., Herrero-Mata, M. J., Balas, A., Vicario, J. L., Sanchez-Garcia, F., Gonzalez-Escribano, M. F., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Ocejo-Vinyals, J. G., Marin, L., Creary, L. E., Osoegawa, K., Vayntrub, T., Caro-Oleas, J. L., Vilches, C., Planelles, D., Fernandez-Vina, M. A. 2019

  Abstract

  Next-generation sequencing (NGS) at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5 loci was performed on 282 healthy unrelated individuals from different major regions of Spain. High-resolution HLA genotypes defined by full sequencing of class I loci and extended coverage of class II loci were obtained to determine allele frequencies and also to estimate extended haplotype frequencies. HLA alleles were typed at the highest resolution level (4-field level, 4FL); with exception of a minor deviation in HLA-DPA1, no statistically significant deviations from expected Hardy Weinberg Equilibrium (HWE) proportions were observed for all other HLA loci. This study provides new 4FL-allele and -haplotype frequencies estimated for the first time in the Spanish population. Furthermore, our results describe extended haplotypes (including the less frequently typed HLA-DPA1 and HLA-DQA1 loci) and show distinctive haplotype associations found at 4FL-allele definition in this Spanish population study. The distinctive allelic and haplotypic diversity found at the 4FL reveals the high level of heterozygosity and specific haplotypic associations displayed that were not apparent at 2-field level (2FL). Overall, these results may contribute as a useful reference source for future population studies, for HLA-disease association studies as a healthy control group dataset and for improving donor recruitment strategies of bone marrow registries. HLA genotyping data of this Spanish population cohort was also included in the 17th International Histocompatibility and Immunogenetics Workshop (IHIW) as part of the study of HLA diversity in unrelated worldwide populations using NGS.

  View details for PubMedID 30763600

• Quality Control Project of NGS HLA Genotyping for the 17th International HLA and Immunogenetics Workshop. Human immunology Osoegawa, K., Vayntrub, T. A., Wenda, S., De Santis, D., Barsakis, K., Ivanova, M., Hsu, S., Barone, J., Holdsworth, R., Diviney, M., Askar, M., Willis, A., Railton, D., Laflin, S., Gendzekhadze, K., Oki, A., Sacchi, N., Mazzocco, M., Andreani, M., Ameen, R., Stavropoulos-Giokas, C., Dinou, A., Torres, M., Dos Santos Francisco, R., Serra-Pages, C., Goodridge, D., Balladares, S., Bettinotti, M. P., Iglehart, B., Kashi, Z., Martin, R., Saw, C. L., Ragoussis, I., Downing, J., Navarrete, C., Chong, W., Saito, K., Petrek, M., Tokic, S., Padros, K., Beatriz Rodriguez, M., Zakharova, V., Shragina, O., Marino, S. R., Brown, N. K., Shiina, T., Suzuki, S., Spierings, E., Zhang, Q., Yin, Y., Morris, G. P., Hernandez, A., Ruiz, P., Khor, S., Tokunaga, K., Geretz, A., Thomas, R., Yamamoto, F., Mallempati, K. C., Gangavarapu, S., Kanga, U., Tyagi, S., Marsh, S. G., Bultitude, W. P., Liu, X., Cao, D., Penning, M., Hurley, C. K., Cesbron, A., Mueller, C., Mytilineos, J., Weimer, E., Bengtsson, M., Fischer, G., Hansen, J. A., Chang, C., Mack, S. J., Creary, L. E., Fernandez-Vina, M. A. 2019

  Abstract

  The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated "consensus" HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB3, HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software.

  View details for PubMedID 30738112

• Tools for Building, Analyzing and Evaluating HLA Haplotypes from Families. Human immunology Osoegawa, K., Mack, S. J., Prestegaard, M., Fernandez-Vina, M. A. 2019

  Abstract

  The highly polymorphic classical human leukocyte antigen (HLA) genes display strong linkage disequilibrium (LD) that results in conserved multi-locus haplotypes. For unrelated individuals in defined populations, HLA haplotype frequencies can be estimated using the expectation-maximization (EM) method. Haplotypes can also be constructed using HLA allele segregation from nuclear families. It is straightforward to identify many HLA genotyping inconsistencies by visually reviewing HLA allele segregation in family members. It is also possible to identify potential crossover events when two or more children are available in a nuclear family. This process of visual inspection can be unwieldy, and we developed the "HaplObserve" program to standardize the process and automatically build haplotypes using family-based HLA allele segregation. HaplObserve facilitates systematically building haplotypes, and reporting potential crossover events. HLA Haplotype Validator (HLAHapV) is a program originally developed to impute chromosomal phase from genotype data using reference haplotype data. We updated and adapted HLAHapV to systematically compare observed and estimated haplotypes. We also used HLAHapV to identify haplotypes when uninformative HLA genotypes are present in families. Finally, we developed "pould", an R package that calculates haplotype frequencies, and estimates standard measures of global (locus-level) LD from both observed and estimated haplotypes.

  View details for PubMedID 30735756

• TRANSETHNIC ANALYSIS OF HIGH-RESOLUTION HLA ALLELES AND COMPLEMENT 4 STRUCTURAL POLYMORPHISMS IN SCHIZOPHRENIA Ollila, H., Li, M., Mindrinos, M., Wang, C., Fernandez-Vina, M., Kuehn, R., Krishnakumar, S., Wilhelmy, J., Tsuang, M. T., Glatt, S. J., Mignot, E., Levinson, D. F. ELSEVIER SCIENCE BV. 2019: S937

  View details for DOI 10.1016/j.euroneuro.2017.08.278

  View details for Web of Science ID 000462156400407

• HLA HHaplotypes In 250 Families: The Baylor Laboratory Results And A Aerspective On A Core NGS Testing Model For The 17th International HLA And Immunogenetics Workshop. Human immunology Askar, M. n., Madbouly, A. n., Zhrebker, L. n., Willis, A. n., Kennedy, S. n., Padros, K. n., Rodriguez, M. B., Bach, C. n., Spriewald, B. n., Ameen, R. n., Shemmari, S. A., Tarassi, K. n., Tsirogianni, A. n., Hamdy, N. n., Mossallam, G. n., Hönger, G. n., Spinnler, R. n., Fischer, G. n., Fae, I. n., Charlton, R. n., Dunk, A. n., Vayntrub, T. A., Halagan, M. n., Osoegawa, K. n., Fernández-Viña, M. n. 2019

  Abstract

  Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

  View details for DOI 10.1016/j.humimm.2019.07.298

  View details for PubMedID 31558329

• Assessment by Extended-Coverage Next-Generation Sequencing Typing of DPA1 and DPB1 Mismatches in Siblings Matching at HLA-A, -B, -C, -DRB1, and -DQ Loci. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Mariano, L. n., Zhang, B. M., Osoegawa, K. n., Lowsky, R. n., Fernandez-Vina, M. n. 2019

  Abstract

  Allogeneic hematopoietic stem cell transplant from an HLA matched sibling donor is usually the preferable choice. The use of next-generation sequencing (NGS) for HLA typing in clinical practice provides broader coverage and higher resolution of HLA genes. We evaluated the frequency of DPB1 crossing-over events among patients and potential related donors typed with NGS. From July 2016 to January 2018, 593 patients and 2385 siblings were typed. We evaluated sibling matching status in 546 patients, and 44.8% of these patients had siblings that matched at HLA-A, -B, -C, -DRB1, and -DQB1 loci. In 306 patient-HLA matched sibling pairs, we found 6 pairs (1.96%) with 1 DPB1 mismatch, and 5 of these pairs included an additional mismatch in DPA1. No additional mismatches were observed at the low expression loci. Using the T cell epitope algorithm, 4 of these DP mismatches were classified as permissive, 1 as nonpermissive in the host-versus-graft direction, and 1 as nonpermissive in the graft-versus-host direction. The frequency of DPB1 and DPA1 mismatches is low, and their impact in related donor transplants is not well established. Although DP typing in related transplants goes beyond guidelines, it is especially relevant for sensitized patients. NGS-based HLA typing provides full gene coverage, and its use in clinical practice can enable better donor selection.

  View details for DOI 10.1016/j.bbmt.2019.07.033

  View details for PubMedID 31381995

• Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population. Human immunology Creary, L. E., Gangavarapu, S. n., Mallempati, K. C., Montero-Martín, G. n., Caillier, S. J., Santaniello, A. n., Hollenbach, J. A., Oksenberg, J. R., Fernández-Viña, M. A. 2019

  Abstract

  The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity.

  View details for DOI 10.1016/j.humimm.2019.07.275

  View details for PubMedID 31345698

• Full-length next-generation sequencing of HLA class I and II genes in a cohort from Thailand HUMAN IMMUNOLOGY Geretz, A., Ehrenberg, P. K., Bouckenooghe, A., Vina, M., Michael, N. L., Chansinghakule, D., Limkittikul, K., Thomas, R. 2018; 79 (11): 773–80

  Abstract

  The human leukocyte antigen (HLA) genes are highly variable and are known to play an important role in disease outcomes, including infectious diseases. Prior knowledge of HLA polymorphisms in a population usually forms the basis for an effective case-control study design. As a prelude to future disease association analyses, we report HLA class I and II diversity in 334 unrelated donors from a Dengue vaccine efficacy trial conducted in Thailand. Long-range PCR amplification of six HLA loci was performed on DNA extracted from saliva samples. HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method presented at the 17th International HLA and Immunogenetics Workshop. In total, we identified 201 HLA alleles, including 35 HLA-A, 57 HLA-B, 28 HLA-C, 24 HLA-DPB1, 21 HLA-DQB1 and 36 HLA-DRB1 alleles. Very common HLA alleles with frequencies greater than 10 percent were A∗11:01:01, A∗33:03:01, A∗24:02:01, B∗46:01:01, C∗07:02:01, C∗01:02:01, C∗08:01:01, DPB1∗05:01:01, DPB1∗13:01:01, DPB1∗04:01:01, DPB1∗02:01:02, DQB1∗03:01:01, DQB1∗05:02:01, DQB1∗03:03:02, DRB1∗12:02:01, DRB1∗09:01:02, and DRB1∗15:02:01. A novel HLA allele, B∗15:450, had a non-synonymous substitution and occurred in more than one donor. Population-based full-length NGS HLA typing is more conclusive and provides a sound foundation for exploring disease association in a given population.

  View details for PubMedID 30243890

• Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop. Human immunology Misra, M. K., Augusto, D. G., Martin, G. M., Nemat-Gorgani, N., Sauter, J., Hofmann, J. A., Traherne, J. A., Gonzalez-Quezada, B., Gorodezky, C., Bultitude, W. P., Marin, W., Vierra-Green, C., Anderson, K. M., Balas, A., Caro-Oleas, J. L., Cisneros, E., Colucci, F., Dandekar, R., Elfishawi, S. M., Fernandez-Vina, M. A., Fouda, M., Gonzalez-Fernandez, R., GroSSe, A., Herrero-Mata, M. J., Hollenbach, S. Q., Marsh, S. G., Mentzer, A., Middleton, D., Moffett, A., Moreno-Hidalgo, M. A., Mossallam, G. I., Nakimuli, A., Oksenberg, J. R., Oppenheimer, S. J., Parham, P., Petzl-Erler, M., Planelles, D., Sanchez-Garcia, F., Sanchez-Gordo, F., Schmidt, A. H., Trowsdale, J., Vargas, L. B., Vicario, J. L., Vilches, C., Norman, P. J., Hollenbach, J. A. 2018

  Abstract

  The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3  KIR3DL1/S1  KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

  View details for PubMedID 30321631

• THE COMMON UNCOMMON EXTENDED HLA HAPLOTYPE: DO TWO WEAK ASSOCIATIONS MAKE IT STRONG? Askar, M. Z., Williams, J. D., Madbouly, A. S., Kang, S., Kennedy, S., Willis, A., Knudsen, T., Robinson, J., Creary, L. E., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 116

  View details for DOI 10.1016/j.humimm.2018.07.132

  View details for Web of Science ID 000444782200127

• EXTENDED HLA HAPLOTYPES IN A GREEK POPULATION BY NGS TECHNOLOGY Tarassi, K., Willis, A., Williams, J. D., Knudsen, T., Robinson, J., Kennedy, S., Kitsiou, V., Osoegawa, K., Kouniaki, D., Athanassiades, T., Fernandez-Vina, M., Tsirogianni, A., Askar, M. Z. ELSEVIER SCIENCE INC. 2018: 117

  View details for DOI 10.1016/j.humimm.2018.07.134

  View details for Web of Science ID 000444782200129

• HLA ALLELE AND HAPLOTYPE FREQUENCIES CHARACTERIZED USING NEXT-GENERATION SEQUENCING METHODS IN UNRELATED WORLD-WIDE POPULATIONS: SUMMARY FROM THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Creary, L. E., Chang, C., Martin, G., Mallempati, K. C., Gangavarapu, S., Osoegawa, K., Vayntrub, T. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 30

  View details for DOI 10.1016/j.humimm.2018.07.029

  View details for Web of Science ID 000444782200025

• NGS CHARACTERIZATION OF EXTENDED HLA HAPLOTYPES IN JAMAICAN FAMILIES FROM THE CARIBBEAN BONE MARROW REGISTRY: A STUDY OF THE 17TH INTERNATIONAL HLA & IMMUNOGENETICS WORKSHOP Askar, M. Z., Charlton, R. K., Dunk, A., Willis, A., Williams, J. D., Knudsen, T., Robinson, J., Kennedy, S., Nelson, W., Geraghty, D., Osoegawa, K., Fernandez-Vina, M. ELSEVIER SCIENCE INC. 2018: 115

  View details for DOI 10.1016/j.humimm.2018.07.131

  View details for Web of Science ID 000444782200126

• THE HLA GENETIC STRUCTURE OF AN ARGENTINIAN REGISTRY POPULATION REFLECT A DIVERGENT DEMOGRAPHIC HISTORY Creary, L. E., Galarza, P., Chang, C., Shields, B., Maha, G. C., Rodriguez Cardozo, M., Osoegawa, K., Vayntrub, T. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 122

  View details for DOI 10.1016/j.humimm.2018.07.142

  View details for Web of Science ID 000444782200137

• Allelic resolution NGS HLA typing of Class I and Class II loci and haplotypes in Cape Town, South Africa. Human immunology Thorstenson, Y. R., Creary, L. E., Huang, H., Rozot, V., Nguyen, T. T., Babrzadeh, F., Kancharla, S., Fukushima, M., Kuehn, R., Wang, C., Li, M., Krishnakumar, S., Mindrinos, M., Fernandez Vina, M. A., Scriba, T. J., Davis, M. M. 2018

  Abstract

  The development of next-generation sequencing (NGS) methods for HLA genotyping has already had an impact on the scope and precision of HLA research. In this study, allelic resolution HLA typing was obtained for 402 individuals from Cape Town, South Africa. The data were produced by high-throughput NGS sequencing as part of a study of T-cell responses to Mycobacterium tuberculosis in collaboration with the University of Cape Town and Stanford University. All samples were genotyped for 11 HLA loci, namely HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4, and -DRB5. NGS HLA typing of samples from Cape Town inhabitants revealed a unique cohort, including unusual haplotypes, and 22 novel alleles not previously reported in the IPD-IMGT/HLA Database. Eight novel alleles were in Class I loci and 14 were in Class II. There were 62 different alleles of HLA-A, 72 of HLA-B, and 47 of HLA-C. Alleles A23:17, A43:01, A29:11, A68:27:01, A01:23, B14:01:01, B15:10:01, B39:10:01, B45:07, B82:02:01 and C08:04:01 were notably more frequent in Cape Town compared to other populations reported in the literature. Class II loci had 21 different alleles of DPA1, 46 of DPB1, 27 of DQA1, 26 of DQB1, 41 of DRB1, 5 of DRB3, 4 of DRB4 and 6 of DRB5. The Cape Town cohort exhibited high degrees of HLA diversity and relatively high heterozygosity at most loci. Genetic distances between Cape Town and five other sub-Saharan African populations were also calculated and compared to European Americans.

  View details for PubMedID 30240896

• BUILDING A HIGH RESOLUTION HAPLOTYPE DATABASE FOR 11 HUMAN LEUKOCYTE ANTIGEN LOCI FROM FAMILY TRIOS Kountouris, E., Levinson, D., Fernandez-Vina, M. A., Ollila, H., Mignot, E., Tsuang, M., Glatt, S., Li, M., Mindrinos, M. WILEY. 2018: 435–36

  View details for Web of Science ID 000430290800240

• HLA ALLELE AND HAPLOTYPE FREQUENCIES CHARACTERIZED USING NEXT-GENERATION SEQUENCING METHODS IN UNRELATED WORLD-WIDE POPULATIONS: SUMMARY FROM THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Creary, L. E., Chang, C., Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Osoegawa, K., Vayntrub, T., Fernandez-Vina, M. A. WILEY. 2018: 327

  View details for Web of Science ID 000430290800012

• HLA HAPLOTYPES IN A GREEK POPULATION BY NGS TECHNOLOGY Tarassi, K., Willis, A., Kitsiou, V., Osoegawa, K., Kouniaki, D., Athanassiades, T., Fernandez-Vina, M., Askar, M., Tsirogianni, A. WILEY. 2018: 412

  View details for Web of Science ID 000430290800188

• HIGH-RESOLUTION CHARACTERIZATION OF ALLELIC AND HAPLOTYPIC HLA FREQUENCIES DISTRIBUTION IN A SPANISH POPULATION USING HIGH-THROUGHPUT NEXT-GENERATION SEQUENCING Montero-Martin, G., Creary, L. E., Mallempati, K., Gangavarapu, S., Vayntrub, T., Planelles, D., Vilches, C., Luis Caro, J., Jose Herrero-Mata, M., Sanchez-Gordo, F., Francisca Gonzalez-Escribano, M., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Sanchez-Garcia, F., Gonzalo Ocejo-Vinyals, J., Balas, A., Luis Vicario, J., Marin, L., Fernandez-Vina, M. A. WILEY. 2018: 424–25

  View details for Web of Science ID 000430290800215

• HIGH RESOLUTION HAPLOTYPE ANALYSES OF CLASSICAL HLA GENES IN FAMILIES FOR THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Osoegawa, K., Creary, L. E., Mallempati, K., Gangavarapu, S., Mack, S. J., Askar, M., Fernandez-Vina, M. WILEY. 2018: 330–31

  View details for Web of Science ID 000430290800019

• BEHCET LIES IN THE EYE OF THE B-HOLDER Elfishawi, S., Mossallam, G., Elfishawi, M., Bruin, H., van de Pasch, L. A. L., Rozemuller, E. H., Zaky, K., Fernandez-Vina, M. A. WILEY. 2018: 460–61

  View details for Web of Science ID 000430290800292

• THE RELEVANCE OF NGS TYPING IN UNRAVELING THE DIVERSITY OF 11 HLA LOCI TYPED IN THE MEXICAN MESTIZOS FROM OAXACA, MEXICO Munguia, A., Creary, L. E., Fernandez-Vina, M. A., Gonzalez, B., Flores-A, H., Gorodezky, C. WILEY. 2018: 440–41

  View details for Web of Science ID 000430290800250

• Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) Creary, L. E., Mallempati, K. C., Gangavarapu, S., Caillier, S. J., Oksenberg, J. R., Fernandez-Vina, M. A. 2018: 1352458518770019

  Abstract

  BACKGROUND: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated.OBJECTIVES: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS.METHODS: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals.RESULTS: HLA-DRB1*15:01:01:01SG (OR=3.20, p