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Martin Maiers - One of the best experts on this subject based on the ideXlab platform.

  • six locus high resolution hla haplotype frequencies derived from mixed resolution dna typing for the entire us donor registry
    Human Immunology, 2013
    Co-Authors: Loren Gragert, Abeer Madbouly, John Freeman, Martin Maiers
    Abstract:

    Abstract We have calculated six-locus high resolution HLA A∼C∼B∼DRB3/4/5∼DRB1∼DQB1 haplotype frequencies using all Be The Match® Registry volunteer donors typed by DNA methods at recruitment. Mixed resolution HLA typing data was inputted to a modified expectation–maximization (EM) algorithm in the form of genotype lists generated by interpretation of primary genomic typing data to the IMGT/HLA v3.4.0 allele list. The full cohort consists of 6.59 million subjects categorized at a broad race level. Overall 25.8% of the individuals were typed at the C locus, and 5.2% typed at the DQB1 locus, while all individuals were typed for A, B, DRB1. We also present a subset of 2.90 million subjects with detailed race/ethnic information mapped to 21 population subgroups, 64.1% of which have primary DNA typing data across at least A, B, and DRB1 loci. Sample sizes at the detailed race level range from 1,242,890 for European Caucasian to 1,376 Alaskan Native or Aleut. Genetic distance measurements show high levels of HLA genetic divergence among the 21 detailed race categories, especially among the eight Asian–American populations. These haplotype frequencies will be used to improve match predictions for donor selection algorithms for hematopoietic stem cell transplantation and improve the accuracy in modeling registry match rates.

  • six locus high resolution hla haplotype frequencies derived from mixed resolution dna typing for the entire us donor registry
    Human Immunology, 2013
    Co-Authors: Loren Gragert, Abeer Madbouly, John Freeman, Martin Maiers
    Abstract:

    Abstract We have calculated six-locus high resolution HLA A∼C∼B∼DRB3/4/5∼DRB1∼DQB1 haplotype frequencies using all Be The Match® Registry volunteer donors typed by DNA methods at recruitment. Mixed resolution HLA typing data was inputted to a modified expectation–maximization (EM) algorithm in the form of genotype lists generated by interpretation of primary genomic typing data to the IMGT/HLA v3.4.0 allele list. The full cohort consists of 6.59 million subjects categorized at a broad race level. Overall 25.8% of the individuals were typed at the C locus, and 5.2% typed at the DQB1 locus, while all individuals were typed for A, B, DRB1. We also present a subset of 2.90 million subjects with detailed race/ethnic information mapped to 21 population subgroups, 64.1% of which have primary DNA typing data across at least A, B, and DRB1 loci. Sample sizes at the detailed race level range from 1,242,890 for European Caucasian to 1,376 Alaskan Native or Aleut. Genetic distance measurements show high levels of HLA genetic divergence among the 21 detailed race categories, especially among the eight Asian–American populations. These haplotype frequencies will be used to improve match predictions for donor selection algorithms for hematopoietic stem cell transplantation and improve the accuracy in modeling registry match rates.

  • the hla dictionary 1999 a summary of hla a b c drb1 3 4 5 dqb1 alleles and their association with serologically defined hla a b c dr and dq antigens
    International Journal of Immunogenetics, 2005
    Co-Authors: G Th M Schreuder, Sge Marsh, Martin Maiers, C K Hurley, M Lau, Craig Kollman, Harriet Noreen
    Abstract:

    This report presents the serologic equivalents of 123 HLA-A, 272 HLA-B, and 155 HLA-DRB1 alleles. The equivalents cover over 64 percent of the presently identified HLA-A, -B, and -DRB1 alleles. The dictionary is an update of the one published in 1999 (Schreuder GMTh, Hurley CK, Marsh SGE, Lau M, Maiers M, Kollman C, Noreen H. The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens. Tissue Antigens 54:407, 1999) and also includes equivalents for HLA-C, DRB3, DRB4, DRB5, and DQB1 alleles. The data summarize information obtained by the WHO Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP), and individual laboratories. In addition, a listing is provided of alleles which are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programs where HLA typings from donors and from recipients on waiting lists represent mixtures of serologic and molecular typings. The tables with HLA equivalents and a questionnaire for submission of serologic reaction patterns for poorly identified allelic products will also be available on the WMDA web page: www.worldmarrow.org.

Jerzy K Kulski - One of the best experts on this subject based on the ideXlab platform.

  • hla drb1 drb3 drb4 and drb5 genotyping at a super high resolution level by long range pcr and high throughput sequencing
    Tissue Antigens, 2014
    Co-Authors: Yuki Ozaki, Shingo Suzuki, Atsuko Shigenari, Yuko Okudaira, Eri Kikkawa, Akira Oka, Masao Ota, Shigeki Mitsunaga, Jerzy K Kulski
    Abstract:

    Super high-resolution single molecule sequence-based typing (SS-SBT) is a human leukocyte antigen (HLA) DNA typing method to the field 4 level of allelic resolution (formerly known as eight-digit typing) to efficiently detect new and null alleles without phase ambiguity by combination of long ranged polymerase chain reaction (PCR) amplification and next-generation sequencing (NGS) technologies. We previously reported the development and application of the SS-SBT method for the eight classical HLA loci, A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1. In this article, we describe the development of the SS-SBT method for three DRB1 linked loci, DRB3, DRB4 and DRB5 (DRB3/4/5) and characterization of DRB1-DRB3/4/5 haplotype structures to the field 4 level. Locus specific PCR primers for DRB3/4/5 were designed to amplify the gene regions from intron 1 to exon 6 [3' untranslated region (3'UTR)]. In total 20 DRB1 and 13 DRB3/4/5 allele sequences were determined by the SS-SBT to the field 4 level without phase ambiguity using 19 DR51, DR52 and DR53 positive genomic DNA samples obtained from Japanese. Moreover, 18 DRB1-DRB3/4/5 haplotypes were estimated to the field 4 level by the SS-SBT method in contrast to 10 haplotypes estimated by conventional methods to the field 1 level (formerly known as two digit typing). Therefore, DRB1-DRB3/4/5 haplotyping by SS-SBT is expected to provide informative data for improved HLA matching in medical research, transplantation procedures, HLA-related disease studies and human population diversity studies.

Mitchell S Cairo - One of the best experts on this subject based on the ideXlab platform.

  • hla dr15 antigen status does not impact graft versus host disease or survival in hla matched sibling transplantation for hematologic malignancies
    Biology of Blood and Marrow Transplantation, 2012
    Co-Authors: Minoo Battiwalla, Kristin Ellis, Steven Z Pavletic, Gorgun Akpek, Peiman Hematti, Thomas R Klumpp, Richard T Maziarz, Bipin N Savani, Mahmoud Aljurf, Mitchell S Cairo
    Abstract:

    The HLA class II DRB1 antigen DR15 is an important prognostic marker in immune-mediated marrow failure states. DR15 has also been associated with favorable outcomes (reduced acute graft-versus-host disease [aGVHD] and relapse) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on transplantation outcomes, we conducted a retrospective study of 2891 recipients of first allogeneic stem cell transplant from HLA-matched sibling donors for the treatment of acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome (MDS) between 1990 and 2007. All patients received conventional myeloablative conditioning, T-replete grafts, and cyclosporine plus methotrexate-based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 patients (25.3%) as positive and 2159 patients (74.7%) as negative for DRB1*15:01 or *15:02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15 positive and negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, aGVHD, chronic GVHD (cGVHD), treatment-related mortality, relapse, disease-free survival, or overall survival (OS). In multivariate analysis, DR15 status showed no significant difference in aGVHD, cGVHD, OS, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplant outcomes in this large and homogenous cohort of patients with leukemia and MDS.

  • hla dr15 antigen status does not impact graft versus host disease or disease free survival in hla matched sibling transplantation for hematologic malignancies
    Blood, 2011
    Co-Authors: Minoo Battiwalla, Kristin Ellis, Steven Z Pavletic, Gorgun Akpek, Peiman Hematti, Thomas R Klumpp, Richard T Maziarz, Bipin N Savani, Mahmoud Aljurf, Mitchell S Cairo
    Abstract:

    Abstract 3094 The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients. Disclosures: No relevant conflicts of interest to declare.

Daniel E. Geraghty - One of the best experts on this subject based on the ideXlab platform.

  • hla high resolution typing by next generation sequencing in pandemrix induced narcolepsy
    PLOS ONE, 2019
    Co-Authors: Alexander Lind, Daniel E. Geraghty, Omar Akel, Madeleine Wallenius, Anita Ramelius, Marlena Maziarz, Lue Ping Zhao, Lars Palm, Ake Lernmark, Helena Elding Larsson
    Abstract:

    The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1. (Less)

  • An integrated genotyping approach for HLA and other complex genetic systems
    Human Immunology, 2015
    Co-Authors: Wyatt C. Nelson, Chul Woo Pyo, David Vogan, Yoon Soo Pyon, Carly Hennessey, Anajane Smith, Ruihan Wang, Shalini Pereira, Akiko Ishitani, Daniel E. Geraghty
    Abstract:

    Clinical immunogenetics laboratories performing routine sequencing of human leukocyte antigen (HLA) genes in support of hematopoietic cell transplantation are motivated to upgrade to next-generation sequencing (NGS) technology by its potential for cost savings as well as testing accuracy and flexibility. While NGS machines are available and simple to operate, there are few systems available that provide comprehensive sample preparation and data analysis workflows to complete the process. We report on the development and testing of the Integrated Genotyping System (IGS), which has been designed to specifically address the challenges associated with the adoption of NGS in clinical laboratories. To validate the system for a variety of sample DNA sources, we have tested 336 DNA specimens from whole blood, dried blood spots, buccal swabs, and lymphoblastoid cell lines. HLA class I and class II genotypes were derived from amplicon sequencing of HLA-A, -B, -C for exons 1-7 and HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4, -DRB5 for exons 1-4. Additionally, to demonstrate the extensibility of the IGS to other genetic loci, KIR haplotyping of 93 samples was carried out in parallel with HLA typing using a workflow based on the HLA system. These results are discussed with respect to their applications in the clinical setting and consequent potential for advancing precision medicine.

Medhat Askar - One of the best experts on this subject based on the ideXlab platform.

  • hla haplotypes in 250 families the baylor laboratory results and a perspective on a core ngs testing model for the 17th international hla and immunogenetics workshop
    Human Immunology, 2019
    Co-Authors: Medhat Askar, Abeer Madbouly, Leah Zhrebker, Amanda Willis, Shawna Kennedy, Karin Padros, Maria Beatriz Rodriguez, Christian Bach, Bernd M Spriewald
    Abstract:

    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.

  • p099 comparison of ssop versus ngs for typing of hla a b c drb1 drb3 b4 b5 dqa1 dqb1 dpa1 dpb1 toward single pass high resolution hla typing in support of solid organ and hematopoietic cell transplant programs
    Human Immunology, 2018
    Co-Authors: Anajane G. Smith, Shalini Pereira, Wyatt Nelson, Andres Jaramillo, Faisal Khan, Noureddine Berka, Marcelo J Pando, Maria Bettinotti, Medhat Askar
    Abstract:

    Aim Many laboratories use a 2-tier HLA typing process: a first pass intermediate resolution and then high resolution, when clinically necessary. SSP or qPCR provide rapid typing for deceased donor workup; SSOP is widely employed for higher volumes; and Sanger sequencing has been the gold standard for high resolution. However, SSOP and Sanger SBT often yield ambiguous results and resolution is expensive and time consuming. Next generation sequencing offers a single pass technology to achieve unambiguous HLA allele assignments. We compared commercial SSOP and NGS systems with respect to accuracy, turnaround time, effort and resolution level. Methods Five laboratories submitted coded, blinded samples, previously typed by SSOP at each institute, to a separate lab for NGS of HLA-A, B, C at exons 1–7, DRB1, DRB3/4/5, DQA1, DQB1, DPB1 at exons 1–4, and DPA1 at exons 2–4. For up to 24 samples by SSOP or up to 48 samples by NGS, benchwork is completed by one technologist on day 1 with results available for reporting on day 2. Results At the SSOP resolution level, results were concordant except for 11 SSOP assignments in 8 specimens due to false probe reactions at DRB1, DRB5, DQA1, DQB1, and DPB1. NGS identified 21 novel sequences: one with a multi-exon deletion and 20 with SNP polymorphisms in HLA-C, DPA1, DPB1, DQA1, DRB1, DRB3, DRB4, and DRB5 alleles. Across the highly polymorphic HLA-A, B, C, DRB1 loci, only 1% of intermediate resolution, IR, SSOP results were unambiguous. Even higher resolution, HR, SSOP by 1 lab gave only 17% specific allele assignments. In contrast, over 99% of NGS results were specific unambiguous genotypes. Across all loci, NGS typing was specific except for certain discrete diploid ambiguities, also found in SSOP. Conclusions This study provides a compelling rationale for implementing NGS for single pass HLA analysis with accurate, 2 day turnaround, which includes the high resolution, unambiguous genotyping critical for unrelated donor HCT and that may be required for sensitized patients with allele specific antibodies. A.G. Smith: 2. Consultant; Company/Organization; Scisco Genetics Inc. S.E. Pereira: 4. Scientific/Medical Advisor; Company/Organization; Scisco Genetics Inc. C. Pyo: 4. Scientific/Medical Advisor; Company/Organization; Scisco Genetics Inc. W. Nelson: 5. Employee; Company/Organization; Scisco Genetics Inc. M. Bettinotti: 3. Speaker’s Bureau; Company/Organization; One Lambda ThermoFisher. M.Z. Askar: 3. Speaker’s Bureau; Company/Organization; Immucor. 4. Scientific/Medical Advisor; Company/Organization; Illumina. D.E. Geraghty: 6. Stock Shareholder; Company/Organization; Scisco Genetics Inc. Download high-res image (283KB) Download full-size image