DQB1 Haplotypes Research Articles

Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DQB1 in Northern Ossetians from Vladikavkaz, Russia

This report shows the HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in a population of 127 healthy Ossetian donors of blood marrow from Vladikavkaz, Russia. First- and second-field (for HLA-C locus) HLA genotyping was performed by polymerase chain reaction sequence-specific priming and/or oligonucleotide probes. Statistical analysis were performed using gene counting and Arlequin software packages. There was no deviation from Hardy-Weinberg equilibrium for all tested loci. The HLA genotypic and haplotypic data of the Ossetians reported here are available in free access at the Allele Frequencies Net Database (http://www.allelefrequencies.net). This data can serve as a reference database for further HLA-based studies in population genetics.

Next Generation Sequencing in HLA haplotype distribution among Telugu speaking population from Andhra Pradesh, India

HLA A:B:C:DRB1:DQB1 allele and haplotype frequencies were determined among India, Andhra Pradesh, Telugu speaking population from South India by Next Generation Sequencing. 180 bone marrow registry donors and 6 cord blood units from Jeevan Stem Cell Foundation (part of Be The Cure Registry), Chennai, Tamilnadu state were included in the study.

HLA-class II haplotypes and Autism Spectrum Disorders

Infections and autoimmunity are associated with autism spectrum disorders (ASD), with both strongly influenced by the genetic regulation of the human leukocyte antigen (HLA) system. The relationship between ASD and the HLA genetic diversity requires further investigation. Using a case control design, the distribution of HLA class II-DRB1 and DQB1 alleles, genotypes and haplotypes were investigated in ASD patients, versus healthy controls (HC). ASD patients meeting DSM-IV TR criteria and HC (474 and 350 respectively) were genotyped at medium resolution using a Luminex-based SSO technology. Comparisons of genotypes, allele frequencies associated with a haplotype analysis were performed. Results indicate: (i) the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders; (ii) the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype. Using the Autism Diagnostic Interview to assess clinical dimensions, higher scores on social (Pc = 0.006) and non-verbal functioning (Pc = 0.004) associated with the DRB1 *11 DQB1*07 haplotype. Our results support HLA involvement in ASD, with possible relevance to GI and gut-brain axis dysregulation.

The distribution of the DRB4*01:03:01:02N null allele in HLA-DRB1~DQB1 haplotypes in the Croatian population.

The aim of the present study was to investigate frequency and haplotype distribution of DRB4 alleles in the Croatian population. The investigated sample consisted of 288 cadaveric donor samples positive for one of the DR53 alleles. HLA-A, -B, -C, -DRB1, and -DQB1 typing was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) low resolution method, while HLA-DRB4 and selected HLA class II specificities typing was performed using PCR-SSP at the allelic level. Three different DRB4 alleles were observed among DRB1*04 samples; DRB4*01:02 (2.38%), DRB4*01:03 (91.27%), and DRB4*01:03:01:02N (6.35%). The DRB4*01:03:01:02N allele was predominantly observed among DRB1*04:02-positive samples, while DRB4*01:02 and DRB4*01:03 alleles did not associate preferably with any of the DRB1*04 subtypes. Among DRB1*04~DRB4~DQB1 haplotypes, the predominant DQB1 allele was DQB1*03:02 (69.94%). Seven different DRB4 alleles were found among DRB1*07:01-positive samples. The analysis of DRB1*07~DRB4~DQB1 haplotypes showed that DRB4*01:03 was found in the majority of HLA-DRB1*07:01~DQB1*02:02 (49.09%) haplotypes while DRB1*07:01~DQB1*03:03 haplotypes carried the DRB4*01:03:01:02N allele almost exclusively (98.21%). Among six DRB1*09:01-positive samples, HLA-DRB1*09:01~DRB4*01:03~DQB1*03:03 was the only detected haplotype. The extended haplotype analysis showed a high frequency of HLA-B*15(B62)~C*03(Cw9)~DRB1*04:02~DRB4*01:03:01:02N~DQB1*03:02 and HLA-B*57~C*06~DRB1*07:01~DRB4*01:03:01:02N~DQB1*03:03 haplotypes. In conclusion, the data presented in this study should prompt other population studies focused on DRB3/4/5 genes and be used as a basis for future investigations of the clinical relevance of these genes in transplantation setting.

HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.

ObjectiveAutoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.MethodsHLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.ResultsThe predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.ConclusionsThe important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.

HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes.

The major histocompatibility complex (MHC) contains the most polymorphic genetic system in humans, the human leukocyte antigen (HLA) genes of the adaptive immune system. High allelic diversity in HLA is argued to be maintained by balancing selection, such as negative frequency-dependent selection or heterozygote advantage. Selective pressure against immune escape by pathogens can maintain appreciable frequencies of many different HLA alleles. The selection pressures operating on combinations of HLA alleles across loci, or haplotypes, have not been extensively evaluated since the high HLA polymorphism necessitates very large sample sizes, which have not been available until recently. We aimed to evaluate the effect of selection operating at the HLA haplotype level by analyzing HLA A~C~B~DRB1~DQB1 haplotype frequencies derived from over six million individuals genotyped by the National Marrow Donor Program registry. In contrast with alleles, HLA haplotype diversity patterns suggest purifying selection, as certain HLA allele combinations co-occur in high linkage disequilibrium. Linkage disequilibrium is positive (Dij'>0) among frequent haplotypes and negative (Dij'<0) among rare haplotypes. Fitting the haplotype frequency distribution to several population dynamics models, we found that the best fit was obtained when significant positive frequency-dependent selection (FDS) was incorporated. Finally, the Ewens-Watterson test of homozygosity showed excess homozygosity for 5-locus haplotypes within 23 US populations studied, with an average Fnd of 28.43. Haplotype diversity is most consistent with purifying selection for HLA Class I haplotypes (HLA-A, -B, -C), and was not inferred for HLA Class II haplotypes (-DRB1 and—DQB1). We discuss our empirical results in the context of evolutionary theory, exploring potential mechanisms of selection that maintain high linkage disequilibrium in MHC haplotype blocks.

Association of DRB1 and DRBQ haplotype 04:01~03:01 with HPV positive head and neck squamous cell carcinoma.

6054 Background: The incidence of human papilloma virus (HPV) associated oropharyngeal head and neck cancer (HNC) is increasing rapidly in the US, Europe, and Asia. HPV16 is etiologic in 90-95% of HPV+ HNC. Sexual transmission and inability to clear infection leading to viral genome integration or chronic presence of episomal HPV16 DNA are precursors to HPV+ HNC carcinogenesis. However it remains unclear why a majority of HPV16 exposed individuals are able to clear the initial infection and avoid the risk of cancer. We hypothesized that difference in the ability eradicate infection may be mediated by certain HLA haplotypes. Methods: HPV(+) HNC patients from the TCGA cohort were HLA-typed based on available exome sequencing data. HLA typing was performed using the ATHLATES algorithm. We compared the distribution of alleles and haplotypes of classical HLA genes (A, C, B, DRB1 and DQB1) among HPV(+) HNC patients with those found in HPV(-) patients. Furthermore we evaluated enrichment of candidate alleles compared to publically available data in Caucasian non-cancer individuals. Results: Out of 528 HNC samples in the TCGA cohort, 450 were of Caucasian ancestry. The DRB1~DQB1 haplotype 04:01~03:01 was significantly increased in HPV(+) HNSCC patients compared to normal, non-cancer individuals ( p-value = 0.0045, OR = 2.52, 95% CI = 1.2–5.03). This was not the case for HPV(-) HNC patients. The number of African American samples in TCGA was comparably small (N = 48, with N = 5 being HPV+) however the frequency of DRB1~DQB1 haplotype 04:01~03:01 in the general African American population is significantly lower. Conclusions: DRB1~DQB1 haplotype 04:01~03:01 associates with an elevated risk for HPV+ HNC. Similar findings were reported 17 years ago for cervical cancer (Br J Cancer, 82(7), 1348–1352), and further validate our findings across tumor types. Mechanistic studies to understand potential DRB1~DQB1 haplotype 04:01~03:01 HPV specific immune dysfunction, as well as evaluation in different risk and racial populations are indicated.

Ancestry of Amerindians and its Impact in Anthropology, Transplantation, HLA Pharmacogenomics and Epidemiology by HLA Study in Wiwa Colombian Population

Background:HLA autosomic genes are unique because they conform the most polymorphic human system. Importance of this system is recognized in Medicine for Transplantation, Epidemiology (HLA and disease linkage), Pharmacogenomics (HLA linked to drug side effects) and for defining the origin of populations in both male and female lineages.Objectives:Studying HLA profile of a isolated Amerindian group from North Colombia (Wiwa) in order to draw conclusions about its Preventive Medicine, the genetic relationship with Worldwide populations and America peopling, since this last issue is hotly debated.Methodology:A total of 14,660 HLA chromosomes were included. Peripheral blood was obtained from volunteer blood donors belonging to Wiwa (also named Arsario) ethnic group. HLA-A, -B, -C, -DRB1 and -DQB1 genes were analyzed by standard methods. Wiwa Amerindians relationships with others were calculated by using Arlequin, Dispan and Vista software computer packages.Results:Extended HLA, -A, -B, -C, -DRB1 and -DQB1 haplotypes have been studied for the first time in this population. Classical Amerindian haplotypes have been found and also new Wiwa (Arsario) Amerindian haplotypes. New haplotypes are A*68:01 - B*15:01 - C*03:03 - DRB1*14:02 - DQB1*03:02, A*11:01 - B*07:02 - C*07:02 - DRB1*15:03 - DQB1*06:02 and A*68:01 - B*15:01 - C*03:04 - DRB1*14:02 - DQB1*03:01.Conclusion:They have been reached after exhaustive comparisons of Wiwa with other Amerindians and Worldwide populations by using genetic distances, Neighbor Joining trees, correspondence analysis and specific group of alleles which are common and frequent in both Amerindians and Pacific Islanders. They are: 1) The Americas First Inhabitants have been probably come through Bering Strait and also through Pacific (from Austronesia and Asia) and Atlantic (from Europe) routes. A bidirectional gene flow is not discarded. 2) Genetic HLA Amerindian profile is separated from that of other Worldwide populations. 3) Amerindians geographical proximity groups’ relatedness is not concordant with HLA genetic relatedness, neither with language. This may be explained by a substantial population decrease that occurred after Europeans invaded America in 1492 and carried new pathogens and epidemics. 4) Our results are also useful for Wiwa and other Amerindians future preventive medicine (HLA linked diseases), HLA pharmacogenomics and transplantation regional programs.

Allorecognition of HLA-C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide-Binding Region Residues, HLA-C Expression, and HLA-DPB1 Disparities.

HLA-C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C MMs, we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56−CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid (aa) MMs in the α1/α2 domains (peptide-binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A-, B-, C-, DRB1-, and DQB1-matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C-mismatched pairs with a positive assay in 52% of the combinations (2.3–18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 MM did not induce any positive alloresponse in five MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic MM. A difference of at least 10 aa residues known to impact peptide/T cell receptor (TCR) binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p = 0.021). The same HLA-C MM, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by 10 or more aas in the peptide/TCR-binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high-risk MMs in unrelated HSCT.

Distribution of HLA DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes among Bahraini women with polycystic ovary syndrome

ObjectiveThis study investigated the association between HLA-DRB1 and –DQB1 alleles and DRB1-DQB1 haplotypes, and polycystic ovary syndrome (PCOS) in Bahraini women. DesignCase-control, retrospective study. MethodsStudy subjects comprised 80 women with PCOS, and 169 age- and ethnically-matched control women. DRB1 and DQB1 genotyping was done by PCR-SSP. ResultsOf the 13 DRB1 alleles and 5 DQB1 alleles identified, DRB1*10 (14.3% vs. 4.4%) and DRB1*14 (8.7% vs. 1.1%), along with DQB1*05 (35.0% vs. 23.9%), were the most frequent alleles in cases, while DRB1*11 (15.3% vs. 6.8%) was the frequent allele found in controls. The association of PCOS with DRB1*10 (Pc<0.001), DRB1*14 (Pc<0.001), DQB1*05 (Pc=0.040), but not DRB1*11 (Pc=0.076) persisted after correcting for multiple comparisons. DRB1-DQB1 haplotype analysis identified nine common shared haplotypes in women with PCOS and control women, with a frequency exceeding 1%. Significantly higher frequency of DRB1*10-DQB1*05 (12.4% vs. 3.1%) and DRB1*14-DQB1*03 (5.6% vs. 1.0%), and reduced frequency of DRB1*11-DQB1*03 (4.1% vs. 14.1%) haplotypes were seen in women with PCOS vs. control women, thus assigning PCOS-susceptible and –protective nature to these haplotypes, respectively. This association persisted after controlling for multiple comparisons. ConclusionOur results confirm an association of HLA-DRB1 and –DQB1 alleles and haplotypes with PCOS susceptibility in Bahraini Arabs, further underscoring the immunological/inflammatory nature of this disorder.

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia

A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p<0.0001), -B (p<0.0001), -DRB1 (p<0.0001) and -DQB1 (p<0.01) loci. Minor deviations from HWEP were detected for HLA-C (p=0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).

HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in a population of 432 healthy unrelated individuals from Albania

This paper reports the HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype polymorphism in a population of 432 healthy individuals from Albania. First-field HLA genotyping was performed by polymerase chain reaction sequence-specific priming and/or oligonucleotide methods. The data were analyzed statistically using gene counting and Arlequin software packages. No deviation from Hardy Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database and they can serve as a reference database for further HLA-based population genetics studies including the Albanian population.

HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients.

The potential impact of human leukocyte antigen (HLA) genotype variations on development of diabetic peripheral neuropathy (DPN) is not well determined. This study aimed to identify the association of HLA class II alleles with DPN in type 2 diabetes (T2D) patients. Totally 106 T2D patients, 49 with DPN and 57 without DPN, and 100 ethnic-matched healthy controls were analyzed. Both groups of the patients were matched based on sex, age, body mass index (BMI) and duration of T2D. Polyneuropathy was diagnosed using electrodiagnostic methods. HLA-DRB1 and DQB1 genotyping was performed in all subjects by the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. T2D patients with DPN showed higher frequencies of HLA-DRB1*10 and DRB1*12 alleles compared to control group (P = 0.04). HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were associated with a decreased risk for developing DPN in T2D patients (P = 0.02 and P = 0.05 respectively). Also, patients with severe neuropathy showed higher frequencies of DRB1*07 (P = 0.003) and DQB1*02 (P = 0.02) alleles than those with mild-to-moderate form of neuropathy. The distribution of DRB1 and DQB1 alleles and haplotypes were not statistically different between all patients and healthy controls. Our findings implicate a possible protective role of HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype against development of peripheral neuropathy in T2D patients. Therefore, variations in HLA genotypes might be used as genetic markers for prediction and potentially management of neuropathy in T2D patients.

High-Resolution Analyses of Human Leukocyte Antigens Allele and Haplotype Frequencies Based on 169,995 Volunteers from the China Bone Marrow Donor Registry Program.

Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High-resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA-DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis studies.

Variation in time and magnitude of immune response and viremia in experimental challenges with Porcine circovirus 2b.

BackgroundPorcine circovirus 2 is the primary agent responsible for inducing a group of associated diseases known as Porcine Circovirus Associated Diseases (PCVAD), which can have detrimental effects on production efficiency as well as causing significant mortality. The objective of this study was to evaluate variation in viral replication, immune response and growth across pigs (n = 974) from different crossbred lines. The approach used in this study was experimental infection with a PCV2b strain of pigs at an average of 43 days of age.ResultsThe sequence of the PCV2b isolate used in the challenge was similar with a cluster of PCV2b isolates known to induce PCVAD and increased mortality rates. The swine leukocyte antigen class II (SLAII) profile of the population was diverse, with nine DQB1 haplotypes being present. Individual viremia and antibody profiles during challenge demonstrate variation in magnitude and time of viral surge and immune response. The correlations between PCV2 specific antibodies and average daily gain (ADG) were relatively low and varied between - 0.14 to 0.08 for IgM and −0.02 and 0.11 for IgG. In contrast, PCV2 viremia was an important driver of ADG decline following infection; a moderate negative correlation was observed between viral load and overall ADG (r = − 0.35, P < 0.001). The pigs with the lowest 10% level of viral load maintained a steady increase in weekly ADG (P < 0.0001) compared to the pigs that had the 10% greatest viral load (P < 0.55). In addition, the highly viremic group expressed higher IgM and IgG starting with d 14 and d 21 respectively, and higher tumor necrosis factor – alpha (TNF-α) at d 21 (P < 0.005), compared to low viremic group.ConclusionsMolecular sources of the observed differences in viremia and immune response could provide a better understanding of the host factors that influence the development of PCVAD and lead to improved knowledge of swine immunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-014-0286-4) contains supplementary material, which is available to authorized users.

Association of HLA class II markers with autoantibody-negative ketosis-prone atypical diabetes compared to type 2 diabetes in a population of sub-Saharan African patients

AimWe investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A− KPD) in comparison to type 2 diabetes (T2D). MethodsA− KPD and T2D sub-Saharan African patients aged 19–63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. ResultsAmong the 130 participants, 35 (27%) were women and 57 (44%) were A− KPD. DRB1 and DQB1 allele frequencies were similar for both A− KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A− KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17–1.85], P=0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79–7.42], P=0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39–1.95], P=0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55–3.96], P=0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P>0.05) in A− KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. ConclusionFactors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A− KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A− KPD.

HLA-A, -B, -C, -DRB1, and -DQB1 Allele Lineages and Haplotype Frequencies among Saudis

There are few reported studies on Saudi population for human leukocyte antigens (HLA) genes. We investigated allele lineages (two-digit) and haplo-type frequencies of HLA-A, -B, -C, -DRB1, and -DQB1 loci in 499 healthy unrelated individuals, selected from potential bone marrow transplant (BMT) families’ donors at King Fahad Medical City (KFMC), Saudi Arabia (SA). Genotyping was performed by Sequence Specific Oligonucleotide Probe (SSOP) utilizing a Luminex-based method. Allele lineages and haplotype frequencies were evaluated along with principal component analysis (PCA) to compare findings with previously reported data on Arab related populations. A total of 18 allele lineages for HLA-A, 28 for -B, 14 for -C, 13 for -DRB1, and 5 for -DQB1 were detected. High values for linkage disequilibrium indicators were found for B:C (D′ = 0.86599) and DRB1:DQB1 (D′ = 0.89468) loci. Additionally, PCA results confirmed previous findings on this population, but also indicated some genetic distances from other Arab related populations. The present study helps in further investigations of this population in anthropological analysis and HLA-associated disease studies.

Human Leukocyte Antigen Class II Haplotypes Affect Clinical Characteristics and Progression of Type 1 Autoimmune Hepatitis in Japan

Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10−10; odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH.

1007-LBP: A Novel Measure of Recipient-Donor HLA Mismatch Predicts Allograft Rejection After Heart Transplantation

It has previously been shown that human leukocyte antigen mismatch (HLAMM) between a transplant recipient and donor at the level of allele groups (previously defined serologically) predicts mortality after heart transplantation. Because HLAMM is not a continuous measure it has limited prognostic value. We sought to develop a novel continuous measure of HLAMM for prediction of allograft rejection using the number of mismatched amino acids in the peptide binding region. Records of patients receiving a heart transplant after 12/31/1999 with at least two recorded values for rejection were identified from the UNOS database. Patients receiving repeat and multi-organ transplants were excluded. A computational algorithm was used to convert allele groups to HLA haplotypes, dervied from the patient’s ethnicity and National Marrow Donor Program haplotype frequency data. The algorithm was validated using a data set of stem cell transplant recipients with high-resolution typing. The algorithm computes the number of mismatched amino acids over exons 2 and 3 for HLA-A and -B, and exon 2 for HLA-DRB1 and -DQB1. We identified 5230 patients in the database. Complete HLA-A, -B, -DRB1, and -DQB1 haplotypes were identified in 3197 patients (61%). HLAMM between patients with and without rejection during follow-up was significantly different for HLA-DRB1 ( p < 0.001), but not significantly different for allele group, HLA-A, -B, or -DQB1. Logistic regression showed that only HLA-DRB1 amino acid mismatch predicted rejection ( p = 0.003). A novel measure of HLAMM is able to predict rejection after heart transplantation. Thus, high-resolution HLA typing of donor and recipient may help predict the risk of allograft rejection after heart transplantation.

HLA-A, -B, -C, -DRB1, and -DQB1 Allele Lineages and Haplotype Frequencies among Saudis

There are few reported studies on Saudi population for human leukocyte antigens (HLA) genes. We investigated allele lineages (two-digit) and haplotype frequencies of HLA-A, -B, -C, -DRB1, and -DQB1 loci in 499 healthy unrelated individuals, selected from potential bone marrow transplant (BMT) families’ donors at King Fahad Medical City (KFMC), Saudi Arabia (SA). Genotyping was performed by Sequence Specific Oligonucleotide Probe (SSOP) utilizing a Luminex-based method. Allele lineages and haplotype frequencies were evaluated along with principal component analysis (PCA) to compare findings with previously reported data on Arab related populations. A total of 18 allele lineages for HLA-A, 28 for -B, 14 for -C, 13 for -DRB1, and 5 for -DQB1 were detected. High values for linkage disequilibrium indicators were found for B:C ( D’ = 0.86599) and DRB1:DQB1 ( D’ = 0.89468) loci. Additionally, PCA results confirmed previous findings on this population, but also indicated some genetic distances from other Arab related populations. The present study helps in further investigations of this population in anthropological analysis and HLA-associated disease studies.