DQB1 Haplotypes Research Articles

A Tool for the Assessment of HLA-DQ Heterodimer Variation in Hematopoietic Cell Transplantation

BackgroundWhen optimizing transplants, clinical decision-makers consider HLA-A, -B, -C, -DRB1 (8 matched alleles out of 8), and sometimes HLA-DQB1 (10 out of 10) matching between the patient and donor. HLA-DQ is a heterodimer formed by the β chain product of HLA-DQB1 and an α chain product of HLA-DQA1. In addition to molecules defined by the parentally-inherited cis haplotypes, α-β trans-dimerization is possible between certain alleles, leading to unique molecules and a potential source of mismatched molecules. Recently, researchers uncovered that clinical outcome after HLA-DQB1-mismatched unrelated donor HCT depends on the total number of HLA-DQ molecule mismatches and the specific α-β heterodimer mismatch. ObjectiveOur objective in this study is to develop an automated tool for analyzing HLA-DQ heterodimer data and validating it through numerous datasets and analyses. By doing so, we provide an HLA-DQ heterodimer tool for DQα-DQβ trans-heterodimer evaluation, HLA-DQ imputation, and HLA-DQ-featured source selection to the transplant field. Study designIn our study, we leverage 352,148 high-confidence, statistically-phased (via a modified expectation-maximization algorithm) HLA-DRB1∼DQA1∼DQB1 haplotypes, 1,052 pedigree-phased HLA-DQA1∼DQB1 haplotypes, and 13,663 historical transplants to characterize HLA-DQ heterodimers data. ResultsUsing our developed QLASSy (HLA-DQA1 and HLA-DQB1 Heterodimers Assessment) tool, we first assessed the data quality of HLA-DQ heterodimers in our data for trans-dimers, missing HLA-DQA1 typing, and unexpected HLA-DQA1 and HLA-DQB1 combinations. Since trans-dimers enable up to four unique HLA-DQ molecules in individuals, we provide in-silico validations for 99.7% of 275 unique trans-dimers generated by 176,074 U.S. donors with HLA-DQA1 and HLA-DQB1 data. Many individuals lack HLA-DQA1 typing, so we developed and validated high-confidence HLA-DQ annotation imputation via HLA-DRB1 with >99% correct predictions in 23,698 individuals. A select few individuals displayed unexpected HLA-DQ combinations. We revisited the typing of 61 donors with unexpected HLA-DQ combinations based on their HLA-DQA1 and HLA-DQB1 typing and corrected 22 out of 61 (36%) cases of donors through data review or retyping and used imputation to resolve unexpected combinations. After verifying the data quality of our datasets, we analyzed our datasets further: we explored the frequencies of observed HLA-DQ combinations to compare HLA-DQ across populations (for instance, we found more high-risk molecules in Asian/Pacific Islander and Black/African American populations), demonstrated the effect of HLA-DQA1 and HLA-DQB1 mismatching on HLA-DQ molecular mismatches, and highlighted where donor selections could be improved at the time of search for historical transplants with this new HLA-DQ information (where 51.9% of G2-mismatched transplants had lower-risk, G2-matched alternatives). ConclusionWe encapsulated our findings into a tool that imputes missing HLA-DQA1 as needed, annotates HLA-DQ (mis)matches, and highlights other important HLA-DQ data to consider for the present and future. Altogether, these valuable datasets, analyses, and a culminating tool serve as actionable resources to enhance donor selection and improve patient outcomes.

Association between HLA alleles and haplotypes with age at diagnosis of type 1 diabetes in an admixed Brazilian population: A nationwide study.

To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-raceand identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.

Family-based association of HLA-DRB1 and DQB1 alleles and haplotypes in a group of Iranian Type 1 diabetes children.

This family-based study was conducted in a group of Iranians with Type 1 diabetes (T1D) to investigate the transmission from parents of risk and non-risk HLA alleles and haplotypes, and to estimate the genetic risk score for this disease within this population. A total of 240 T1D subjects including 111 parent-child trios (111 children with T1D, 133 siblings, and 222 parents) and 330 ethnically matched healthy individuals were recruited. High-resolution HLA typing for DRB1/DQB1 loci was performed for all study subjects (n = 925) using polymerase chain reaction-sequence-specific oligonucleotide probe method. The highest predisposing effect on developing T1D was conferred by the following haplotypes both in all subjects and in probands compared to controls: DRB1*04:05-DQB1*03:02 (Pc = 2.97e-06 and Pc = 6.04e-10, respectively), DRB1*04:02-DQB1*03:02 (Pc = 5.94e-17 and Pc = 3.86e-09, respectively), and DRB1*03:01-DQB1*02:01 (Pc = 8.26e-29 and Pc = 6.56e-16, respectively). Conversely, the major protective haplotypes included DRB1*13:01-DQB1*06:03 (Pc = 6.99e-08), DRB1*15:01-DQB1*06:02 (Pc = 2.97e-06) in the cases versus controls. Also, DRB1*03:01-DQB1*02:01/DRB1*04:02|05-DQB1*03:02 and DRB1*03:01-DQB1*02:01/DRB1*03:01-DQB1*02:01 diplotypes conferred the highest predisposing effect in the cases (Pc = 8.65e-17 and Pc = 6.26e-08, respectively) and in probands (Pc = 5.4e-15 and Pc = 0.001, respectively) compared to controls. Transmission disequilibrium test showed that the highest risk was conferred by DRB1*04:02-DQB1*03:02 (Pc = 3.26e-05) and DRB1*03:01-DQB1*02:01 (Pc = 1.78e-12) haplotypes and the highest protection by DRB1*14:01-DQB1*05:03 (Pc = 8.66e-05), DRB1*15:01-DQB1*06:02 (Pc = 0.002), and DRB1*11:01-DQB1*03:01 (Pc = 0.0003) haplotypes. Based on logistic regression analysis, carriage of risk haplotypes increased the risk of T1D development 24.5 times in the Iranian population (p = 5.61e-13). Also, receiver operating characteristic curve analysis revealed a high predictive power of those risk haplotypes in discrimination of susceptible from healthy individuals (area under curve: 0.88, p = 5.5e-32). Our study highlights the potential utility of genetic risk assessment based on HLA diplotypes for predicting T1D risk in individuals, particularly among family members of affected children in our population.

Development and characterization of a cell donor registry for virus-specific T cell manufacture in a blood bank.

Adoptive cell therapy using virus-specific T cells (VST) is a strategy for treating common opportunistic viral infections after transplantation, particularly when these infections do not resolve through antiviral drug therapy. The availability of third-party healthy donors allows for the immediate use of cells for allogeneic therapy in cases where patients lack an appropriate donor. Here, we present the creation of a cell donor registry of human leukocyte antigen (HLA)-typed blood donors, REDOCEL, a strategic initiative to ensure the availability of compatible cells for donation when needed. Currently, the registry consists of 597 healthy donors with a median age of 29 years, 54% of whom are women. The most represented blood groups were A positive and O positive, with 36.52% and 34.51%, respectively. Also, donors were screened for cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Almost 65% of donors were CMV-seropositive, while less than 5% were EBV-seronegative. Of the CMV-seropositive donors, 98% were also EBV-seropositive. High-resolution HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies were determined in the registry. Prevalent HLA alleles and haplotypes were well represented to ensure donor-recipient HLA-matching, including alleles reported to present viral immunodominant epitopes. Since the functional establishment of REDOCEL, in May 2019, 87 effective donations have been collected, and the effective availability of donors with the first call has been greater than 75%. Thus, almost 89% of patients receiving an effective donation had available at least 5/10 HLA-matched cell donors (HLA-A, -B, -C, -DRB1, and -DQB1). To summarize, based on our experience, a cell donor registry from previously HLA-typed blood donors is a useful tool for facilitating access to VST therapy.

Ethinicity-dependent association of HLA DRB1∼DQB1 haplotype in Brazilian narcolepsy patients and review of the literature

Ethinicity-dependent association of HLA DRB1∼DQB1 haplotype in Brazilian narcolepsy patients and review of the literature

Diversity of HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes in Kazakhstani Tatar population and genetic relatedness to other populations

BackgroundKazakhstan is a transcontinental former Soviet Union republic whose present-day population comprises more than 100 ethnic groups. Insofar as Human Leukocyte Antigen (HLA) genotyping is useful for anthropological studies, data on the HLA profile of Kazakhstani Tatars are lacking. ObjectiveWe extend our earlier findings on the unique HLA profile of distinct Kazakhstani populations by examining HLA class I and class II loci in Kazakhstani (Volga) Tatar minority population and its relatedness to those of bordering and worldwide communities. MethodsHLA class I and class II genotypes of the Kazakhstan Tatar minority were analyzed by PCR-SSP and were compared to neighboring populations using Neighbor-Joining (NJ) trees and standard genetic distances (SGD) analysis. ResultsIn total, 132 HLA alleles were identified in a sample of 103 Kazakhstani Tatars, of which HLA-A*02:01 (20.1 %), -B*07:02 (12.1 %), -C*07:02 (12.7 %), -DRB1*07:01 (18.1 %), and -DQB1*02:01 (19.6 %) were the most frequent. The most frequent two-locus haplotypes were B*07:02 ∼ C*07:02 (10.6 %) B*07:02 ∼ DRB1*15:01 (06.1 %), B*07:02 ∼ DQB1*06:02 (07.1 %), and DRB1*15:01 ∼ DQB1*06:02 (11.6 %). ConclusionsConsidering historical data, the close relatedness of Kazakhstani Tatars to European Russians (including Russian Tatars) suggests that Kazakhstani Tatars may be Russian Tatars, who originated from the Volga region, following their massive migrations to central Asia.

Investigating associations between HLA DQA1 ~ DQB1 haplotypes, H. pylori infection, metaplasia, and anti-CagA IgA seropositivity in a Turkish gastritis cohort.

Helicobacter pylori was reported as an important cause of gastritis, and gastric ulcers and CagA oncoprotein-producing H. pylori subgroups were blamed to increase the severity of gastritis. Disparities were reported in that the presence of serum anti-CagA IgA was not parallel with CagA-positive H. pylori cohabitation. We hypothesized that the HLA-DQA1 ~ DQB1 haplotypes in human populations include protective haplotypes that more effectively present immunogenic CagA peptides and susceptible haplotypes with an impaired capacity to present CagA peptides. We recruited patients (n = 201) admitted for gastroendoscopy procedures and performed high-resolution HLA-DQA1 and DQB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.0% positive), and H. pylori was classified as positive or negative in gastric mucosal tissue slides (72.6% positive). The HLA DQA1*05:05 allele (29.1%) and HLA DQB1*03:01 allele (32.8%) were found at the highest frequency among gastritis patients of Turkish descent. In HLA DQA1*05:05 ~ DQB1*03:01 double homozygous (7.3%) and heterozygous (40.7%) haplotype carriers, the presence of anti-CagA IgA decreased dramatically, the presence of H. pylori increased, and the presence of metaplasia followed a decreasing trend. The DQ protein encoded by HLA DQA1*05:05-DQ*03:01 showed a low binding affinity to the CagA peptide when binding capacity was analyzed by the NetMHCIIPan 4.0 prediction method. In conclusion, HLA DQA1 ~ DQB1 polymorphisms are crucial as host defense mechanisms against CagA H. pylori since antigen binding capacity plays a crucial role in anti-CagA IgA production.

The Association of Human Leukocyte Antigen Genotyping Among Sudanese Patients With Rheumatoid Arthritis: Reference to Ethnicity.

Human leukocyte antigens (HLA) account for up to one-half of the total genetic contribution to rheumatoid arthritis (RA) risk. The study investigated the association of HLA class II genotyping with RA susceptibility in Sudanese ethnic groups. The DRB1 and DQB1 alleles and haplotypes were determined in 122 RA patients (i.e., Gaalia = 54, Johayna = 24, Baggara = 17, Nile Nubian = 12, and others = 15) and 120 healthy controls ofethnic groups (i.e., Gaalia = 44, Johayna = 11, Baggara = 15, Nile Nubian = 9, and others = 21) using a polymerase chain reaction with sequence-specific primers method. Susceptibility to RA was associated with a high frequency of DRB1*04(P = 0.04), DRB1*10(P = 0.04), and DQB1*03(P= 2.2 x 10-8/Pc = 6.6 x 10-8) between study ethnic groups, while protective effects were shown with DRB1*07(P= 0.01), DQB1*02(P= 0.02), andDQB1*06(P= 2.2 x 10-6/Pc= 6.6 x 10-6), with an inconsistent frequency between study ethnic groups.The HLA haplotypes that were high in frequency among RA ethnic groups and showed susceptibility associations were DRB1*03-DQB1*03,DRB1*04-DQB1*03,DRB1*08-DQB1*03, DRB1*13-DQB1*02,and DRB1*13-DQB1*03 (P= 0.00003/Pc = 0.0003,P= 0.0001/Pc= 0.0001,P= 0.03, P= 0.004/Pc= 0.03, and P= 3.79x10-8/Pc= 3.3x10-9,respectively). On the contrary, DRB1*03-DQB1*02,DRB1*07-DQB1*02, andDRB1*13-DQB1*06 were lower in frequency in the ethnic groups with RA and may confer protection (P= 0.004/Pc= 0.032,P= 0.002/Pc= 0.02, and P= 0.01, respectively). Our findings indicate an association between HLA-DRB1 and DQB1 genotypes and the susceptibility to RA in the Sudanese population, with a moderate frequency between our ethnic groups.

The HLA profile and genetic affinities of three primitive Tamil-speaking endogamous groups: Kallars of Thanjavur, Piramalai Kallar and Vanniyar

BackgroundThe present study was aimed to study the frequencies of HLA-DRB1/-DQB1 alleles and haplotypes of three endogamous groups of Tamil Nadu state, South India. PCR-SSP typing of HLA-DRB1 and -DQB1 alleles were performed on 111 Kallars of Thanjavur, 80 Piramalai Kallar of Madurai and 119 Vanniyar. Genetic distances, neighbor-joining phylogenetic dendrograms and correspondence analysis have been performed.ResultsThe HLA class II alleles, DRB1*07 (25.2%), DRB1*15 (15.7%), DRB1*14 (11.7%) and DRB1*12 (9.90%) among Kallars of Thanjavur; DRB1*15 (28.7%), DRB1*04 (15.6%), DRB1*10 (14.3%), DRB1*13 (11.2%) and DRB1*03 (9.37%) among Piamalai Kallar and DRB1*15 (24.7%), DRB1*04 (15.9%), DRB1*07 (11.7%), DRB1*12 (11.3%) and DRB1*10 (10.0%) among Vanniyar were more frequent. Similarly, alleles DQB1*06 (31.0%), DQB1*02 (26.5%) and DQB1*05 (24.7%) among Kallars of Thanjavur; DQB1*05 (32.5%), DQB1*06 (31.8%), DQB1*02 (16.2%) and DQB1*03:02 (12.5%) among Piramalai Kallar and DQB1*05 (52.9%), DQB1*06 (22.6%) and DQB1*02 (11.3%) among Vanniyar were more frequent. We genotyped the two most frequent two-locus haplotypes, such as DRB1*15-DQB1*06 and DRB1*07-DQB1*02 for HLA-A/-B/–C alleles to identify the 5-locus extended haplotypes to extrapolate global affinities. We identified a number of five locus extended haplotypes among south Indian population with stronger global affinities. Further, we identified the presence of a highly unique extended haplotypes such as A*11-B*35-C*12-DRB1*07-DQB1*02 (HF:0.1458) in Kallars of Thanjavur, A*03-B*35-C*04-DRB1*15-DQB1*06 (HF:0.1833) in Piramalai Kallar and A*03-B*07-C*07-DRB1*15-DQB1*06 (HF: 0.1800) in Kallars of Thanjavur and (HF: 0.1081) in Vanniyar population.ConclusionsAllele distribution and haplotype analysis have demonstrated that the Kallars of Thanjavur, Piramalai Kallar and Vanniyar populations shared HLA alleles with other ethnic and other Indian populations, while showing population specific haplotypes. Analysis of population-specific distribution of HLA alleles is proved to be important in finding out the relatedness of the ethnic groups across continents. The extensive polymorphism of the HLA system also has useful application in the study of the origin, evolution and migration patterns of human populations.

HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in Lebanese and their relatedness to neighboring and distant populations

BackgroundThis study examined the origin of present-day Lebanese using high-resolution HLA class I and class II allele and haplotype distributions. The study subjects comprised 152 unrelated individuals, and their HLA class I and class II alleles and two-locus and five-locus haplotypes were compared with those of neighboring and distant communities using genetic distances, neighbor-joining dendrograms, correspondence, and haplotype analyses. HLA class I (A, B, C) and class II (DRB1, DQB1) were genotyped at a high-resolution level by PCR-SSP.ResultsIn total, 76 alleles across the five HLA loci were detected: A*03:01 (17.1%), A*24:02 (16.5%), B*35:01 (25.7%), C*04:01 (25.3%), and C*07:01 (20.7%) were the most frequent class I alleles, while DRB1*11:01 (34.2%) and DQB1*03:01 (43.8%) were the most frequent class II alleles. All pairs of HLA loci were in significant linkage disequilibrium. The most frequent two-locus haplotypes recorded were DRB1*11:01 ~ DQB1*03:01 (30.9%), B*35:01-C*04:01 (20.7%), B*35:01 ~ DRB1*11:01 (13.8%), and A*24:02 ~ B*35:01 (10.3%). Lebanese appear to be closely related to East Mediterranean communities such as Levantines (Palestinians, Syrians, and Jordanians), Turks, Macedonians, and Albanians. However, Lebanese appear to be distinct from North African, Iberian, and Sub-Saharan communities.ConclusionsCollectively, this indicates a limited genetic contribution of Arabic-speaking populations (from North Africa or the Arabian Peninsula) and Sub-Saharan communities to the present-day Lebanese gene pool. This confirms the notion that Lebanese population are of mixed East Mediterranean and Asian origin, with a marked European component.

HLA Genotyping in Romanian Adult Patients with Celiac Disease, their First-degree Relatives and Healthy Persons.

Celiac disease is characterized by an inappropriate T-cell-mediated response to gluten in small bowel in genetically predisposed individuals, carriers of the DQ2 and/or DQ8 haplotypes of the human leukocyte antigen. The aim of our study was to asses HLA typing in adult patients with celiac disease, in their first degree relatives and in a healthy control group. We conducted a prospective observational study on three cohorts: 117 patients diagnosed with celiac disease, 41 first-degree relatives of celiac patients and 57 asymptomatic healthy volunteers. Low resolution HLA typing forDQ alleles was performed in all study subjects with DNA extracted from peripheral blood, using SSP HLA-DQB1 kit (Innotrain Diagnostik GmbH, Germany).Next Generation Sequencing (NGS) was used only in 18 patients for typing confirmation of DQB1 and DQA1 loci and whole gene sequencing. Prevalence of HLA-DQ2 was significantly higher in the CD group compared to the healthy subjects group (95.6% vs 29.8%, p <0.001), with no statistically significant differences in HLA-DQ8 and combined HLA-DQ2/DQ8 prevalences.Several HLA DQA1 and DQB1 alleles (HLA-DQA1* 05:01, HLA-DQB1*02:01, HLA-DQB1*02:02) and haplotypes (DQA1*02:01-DQB1*02:02,DQA1*05:01-DQB1*02:01) were strongly associated with celiac disease in our group: OR 4.28, 4.28, 4.67 and 5.43 and 4.28 respectively. Predominantly, patients presented with typical symptoms and iron deficiency anemia. 95.5% of them had histological Marsh type modifications ≥3a. A relatively poor response to gluten-free diet was observed and 9.4% developed complications (refractory celiac disease, enteropathy-associated T cell lymphoma, intestinal adenocarcinoma), with a death rate of 6.8%. 23% associated other autoimmune diseases.Screening adherence for 1st degree relatives was very low: only 16%. Familial screening diagnosed 4 cases of asymptomatic celiac disease. 32 relatives (78%) had HLA-DQ2 haplotype, 5 carried HLA-DQ8, 4 didn't carry any risk haplotype. This study demonstrated a higher prevalence of the HLA-DQ2 genotype in patients with celiac disease compared to the healthy population but not of HLA-DQ8 or combined HLA-DQ2/DQ8. Alleles HLA-DQA1* 05:01, HLA-DQB1*02:01, HLA-DQB1*02:02 and haplotypes (DQA1*02:01-DQB1*02:02,DQA1*05:01-DQB1*02:01) were strongly associated with celiac disease in our cohort.

Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens.

IntroductionType 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (β-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development.ObjectivesWe aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10).MethodsAccordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes.ResultsThe frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (cp = 0.0065), as did their codominant (cp = 0.026) and recessive (cp = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB1*03 (pc < 0.0013), DRB1*04 (cp = 0.0169), DQA1*03 (cp = 0.0222), DQA1*05 (cp < 0.0006), DQB1*02 (cp = 0.0005), and DQB1*06 (cp < 0.0005). And lower frequencies were observed for: DRB1*07 (cp = 0.0078), DRB1*11 (cp = 0.0013), DRB1*13 (cp < 0.0364), DRB1*15 (cp < 0.0013), DQA1*01 (cp < 0.0006), and DQA1*02 (cp = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024).ConclusionThis study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.

HLA-DRB1 and -DQB1 Alleles, Haplotypes and Genotypes in Emirati Patients with Type 1 Diabetes Underscores the Benefits of Evaluating Understudied Populations.

Background: HLA class II (DR and DQ) alleles and antigens have historically shown strong genetic predisposition to type 1 diabetes (T1D). This study evaluated the association of DRB1 and DQB1 alleles, genotypes, and haplotypes with T1D in United Arab Emirates. Materials and Methods: Study subjects comprised 149 patients with T1D, and 147 normoglycemic control subjects. Cases and controls were Emiratis and were HLA-DRB1 and -DQB1 genotyped using sequence-based typing. Statistical analysis was performed using Bridging Immunogenomic Data-Analysis Workflow Gaps R package. Results: In total, 15 DRB1 and 9 DQB1 alleles were identified in the study subjects, of which the association of DRB1*03:01, DRB1*04:02, DRB1*11:01, DRB1*16:02, and DQB1*02:01, DQB1*03:02, DQB1*03:01, and DQB1*06:01 with altered risk of T1D persisted after correcting for multiple comparisons. Two-locus haplotype analysis identified DRB1*03:01∼DQB1*02:01 [0.44 vs. 0.18, OR (95% CI) = 3.44 (2.33–5.1), Pc = 3.48 × 10−10]; DRB1*04:02∼DQB1*03:02 [0.077 vs. 0.014, OR = 6.06 (2.03–24.37), Pc = 2.3 × 10−3] and DRB1*04:05∼DQB1*03:02 [0.060 vs. 0.010, OR = 6.24 (1.79–33.34), Pc = 0.011] as positively associated, and DRB1*16:02∼DQB1*05:02 [0.024 vs. 0.075, OR = 0.3 (0.11–0.74), Pc = 0.041] as negatively associated with T1D, after applying Bonferroni correction. Furthermore, the highest T1D risk was observed for DR3/DR4 [0.104 vs. 0.006, OR = 25.03 (8.23–97.2), Pc = 2.6 × 10−10], followed by DR3/DR3 [0.094 vs. 0.010, OR = 8.72 (3.17–25.32), Pc = 3.18 × 10−8] diplotypes. Conclusion: While DRB1 and DQB1 alleles and haplotypes associated with T1D in Emiratis showed similarities to Caucasian and non-Caucasian populations, several alleles and haplotypes associated with T1D in European, African, and Asian populations, were not observed. This underscores the contribution of ethnic diversity and possible diverse associations between DRB1 and DQB1 and T1D across different populations.

Helicobacter pylori infection and disease severity in multiple sclerosis patients: Is there a link with HLA alleles?

Backgrounds: Environmental factors such as bacterial infections, as well as genetic factors—in particular the human leukocyte antigen (HLA) alleles—have been implicated in the etiology of multiple sclerosis (MS). This study aims to explore the relationship between Helicobacter pylori infection, HLA alleles, and disease severity in Iranian MS patients. Methods: The study population comprised 125 MS patients and 153 ethnically matched healthy controls. Stool antigen test was used to detect H. pylori, and the expanded disability status scale (EDSS) scores were assessed in the patients. HLA-DRB1 and DQB1 alleles and haplotypes were determined in both the patients and the controls. The relationships between H pylori infection, HLA alleles, and EDSS were also analyzed. Results: HLA-DRB1*15 and DQB1*06 alleles families and the DRB1*15~DQB1*06 haplotype were significantly more frequent in MS patients, whereas HLA-DRB1*14 and DRB1*14~DQB1*05 haplotype were less frequent. Of the 125 MS patients, 38 were diagnosed with active H. pylori infection. We found lower frequencies of HLA-DRB1*15 (P = .08) and DRB1*16 (P = .05) alleles and a higher frequency of DQB1*02 (P = .06) in the H. pylori-positive patients. HLA-DRB1*07 was more prevalent in patients with EDSS≤3.0 (P = .06). More severe MS cases (EDSS&gt;3.0) were linked to H pylori positivity (P = .02), disease chronicity (P = .001), receiving non-steroidal anti-inflammatory drugs (P = .02), and female gender (P = .05). Conclusion: These preliminary findings suggest a link between H. pylori infection and the severity of MS H. pylori-positive patients regardless of the type of HLA carriage.

The polymorphism of HLA-A, -C, -B, -DRB3/4/5, -DRB1, -DQB1 loci in Zhejiang Han population, China using NGS technology.

The distributions of HLA allele and haplotype are various in the populations. Currently, the data for HLA alleles and haplotypes at three fields resolution level in Chinese Han population is rare. Here, the HLA alleles and haplotypes of the 1734 cord blood samples from Zhejiang Han population, China were reported at three fields resolution. All samples were randomly collected from the Zhejiang Cord Blood Bank, China. HLA-A, -B, -C, -DRB1, -DQB1, -DRB3/4/5 loci was genotyped using next generation sequencing method. The genotypes of the samples were assigned using the HLA TypeStream Visual Software version 1.2.0. The frequency of alleles, haplotype estimation and linkage disequilibrium analysis were performed with the Arlequin software 3.5.2.2. It was found that the top three frequent alleles of HLA-A, -B, -C, -DRB1, -DQB1, -DRB3/4/5 loci were A*11:01:01 (25.81%), A*24:02:01 (16.70%), A*02:01:01 (10.61%); B*40:01:02 (15.97%), B*46:01:01 (11.48%), B*58:01:01 (7.96%); C*07:02:01 (19.03%), C*01:02:01 (17.65%), C*03:04:01 (10.41%); DRB1*09:01:02G (17.96%), DRB1*12:02:01 (9.57%), DRB1*08:03:02 (9.54%); DQB1*03:01:01G (21.05%), DQB1*03:03:02 (19.15%), DQB1*06:01:01G (12.08%); DRB4*01:03:01 (25.72%), DRB3*02:02:01 (20.27%), DRB5*01:01:01 (10.96%), respectively. A total of 1528 distinct A∼C∼B∼DRB3/4/5∼DRB1∼DQB1 haplotypes were estimated, and the top three most common haplotypes were A*33:03:01∼C*03:02:02∼B*58:01:01∼DRB3*02:02:01∼DRB1*03:01:01∼ DQB1*02:01:01 (4.02%), A*30:01:01∼C*06:02:01∼B*13:02:01∼DRB4*01:03:01∼ DRB1*07:01:01 ∼DQB1*02:02:01 (3.11%) and A*02:07:01∼C*01:02:01∼B*46:01:01 ∼DRB4*01:03:01∼DRB1*09:01:02G∼DQB1*03:03:02 (3.05%). Some alleles of different HLA loci were shown strong linkage disequilibrium. In conclusion, the data of allele and haplotype of HLA-A, -B, -C, -DRB1, -DQB1 and -DRB3/4/5 loci at three fields resolution level were obtained in Zhejiang Han population, thus contributing to analyze the HLA ploymorphism in the populations.

Human Leukocyte Antigen DQ (HLA‐DQ) genotypes and haplotypes and their association with phenotype in patients with celiac disease in India

Background and AimHuman Leukocyte Antigen DQ (HLA‐DQ) genotypes play a permissive role in the genesis of celiac disease (CeD). In this case–control study, we used next‐generation sequencing to determine HLA‐DQA1 and ~DQB1 genotypes and haplotypes associated with CeD in Indian patients.MethodsHLA‐DQA1 and ~DQB1 loci were amplified, using long‐range polymerase chain reaction (PCR), from DNA of 259 patients with symptomatic CeD (160 typical and 99 atypical), 45 asymptomatic CeD, 96 potential CeD, and 300 healthy adults. Amplicons were fragmented and sequenced on the Illumina platform, and alleles and haplotypes were assigned by matching against the HLA‐international ImMunoGeneTics (IMGT) database.ResultsHLA‐DQA1*05:01 (odds ratio [OR] 8.39, 95% confidence interval [CI] 5.64–12.47) and HLA‐DQB1*02:01 (OR 8.59, 95% CI 5.75–12.83) were the genotypes that showed a risk association with symptomatic CeD. Among the haplotypes, HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (OR 8.56, 95% CI 5.67–13.19) showed a strong risk association with symptomatic CeD. When comparing symptomatic CeD with subclinical forms (asymptomatic and potential) CeD, HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (OR 2.34, 95% CI 1.61–3.43) was significantly associated with risk of symptomatic disease. The strength of association between the HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 haplotype and the CeD phenotype showed a gradient in the order typical > atypical > asymptomatic > potential CeD. Genotypes consistent with expression of HLA DQ2 and/or 8 were noted in 128 (80%) typical, 73 atypical (74%), 27 (60%) asymptomatic, and 52 (54%) potential CeD participants.ConclusionHLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (haplotype DQ2.5) showed a very strong risk association with symptomatic CeD in Indian patients. The strength of association showed a gradient of increase from potential to typical CeD, coinciding with a phenotypic change in the celiac iceberg.

Relevance of autoantibody profile with HLA-DRB1 and -DQB1 alleles in a group of Iranian systemic lupus erythematosus patients

BackgroundOne of the most relevant genetic components in systemic lupus erythematosus (SLE) is human leukocyte antigen (HLA) gene complex which plays a central role in autoimmune responses. This study aimed to explore the associations of HLA-DRB1/-DQB1 alleles and haplotypes with SLE risk and the appearance of autoantibodies in SLE disease. MethodsA total of 127 SLE patients and 153 ethnically matched healthy controls were enrolled. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSP method and then HLA alleles and haplotypes frequencies were compared between two groups and among the patients in terms of autoantibodies spectrum. ResultsWe found that HLA-DRB1*03 and HLA-DRB1*16 alleles were significantly associated with increased risk (P = 0.008, PC=0.05 and P = 0.002, PC=0.02 respectively) and DRB1*01 conferred a potential protective role for disease (P = 0.03, PC=0.13). Similar associations were observed at haplotype level; DRB1*03~DQB1*02 (OR1.91,P = 0.01, PC=0.08), DRB1*16~DQB1*05 (OR3.65,P = 0.004,PC=0.06) and DRB1*01~DQB1*05 (OR0.36,P = 0.04, PC=0.22). Remarkably, we observed significantly associations of DRB1*03 with the appearance of anti-SSA/Ro (PC=0.02), anti-SSB/La (PC=0.002) and anti-coagulant (P = 0.007), DRB1*15 with anti-SSA/Ro (PC=0.04), DRB1*16 with anti-Sm (PC=0.02), DRB1*04 with anti-β2gpI (PC=3 * 10−5), anti-cardiolipin (P = 0.002) and rheumatoid factor (P = 0.004) and DRB1*13 with anti-Sm (PC=0.02) and anti-β2gpI (PC=0.01) antibodies. Also, negative associations of DRB1*04 with anti-Sm, anti-SSA/Ro, DQB1*03 with anti-Sm and DRB1*11 with anti-Sm and anti-β2gpI were observed. ConclusionsWe identified DRB1*03 and DRB1*16 as risk alleles and DRB1*01 as a potential protective allele for SLE disease. More importantly, we found a close link between genetic susceptibility for SLE and autoantibodies status that was more evident for DRB1*03 allele.

Dog leukocyte antigen (DLA) class II genotypes associated with chronic enteropathy in French bulldogs and miniature dachshunds

Canine chronic enteropathy (CE) is a group of immunogenetic disorders of unclear etiology characterized by chronic or recurrent gastrointestinal signs and inflammation. Diagnosis of CE subtypes by treatment response is a lengthy and challenging process, particularly in refractory cases of the disease. Given known association of dog leukocyte antigen (DLA) class II genotype and various immunogenetic disorders between and across breeds, this study was designed to examine the potential of determining susceptibility to refractory CE through identification of risk and protective genotypes in French bulldogs and miniature dachshunds—two popular dog breeds in Japan.Sequence-based genotyping of three DLA class II genes in 29 French bulldogs and 30 miniature dachshunds with refractory CE revealed a protective haplotype DLA-DRB1*002:01-DQA1*009:01-DQB1*001:01 against CE in French bulldogs (OR 0.09, 95 % CI 0.01−0.71, p = 0.0084). No statistical difference was noted between miniature dachshund cases and controls. These findings, largely disparate from a previous study on German shepherd dogs in the UK, were taken as possible indication of etiological differences in the refractory CE noted between and within breeds, and by extension, the potential of identifying such disease heterogeneity by DLA typing.The DLA-DQA1/DQB1 haplotype, protective against CE in our French bulldogs, has been reported as protective in various immune-mediated disorders such as Doberman hepatitis (Dyggve et al., 2011). Likewise, the DLA-DRB1*006:01 risk allele for Doberman hepatitis was noted in more French bulldogs with CE compared to controls, in line with reports on genotypes associated with both risk and protection being shared across various autoimmune diseases and breeds.These findings support an immunogenetic basis to the French bulldog-CE in our analysis, calling for further DLA studies working with larger samples and different breeds towards phenotypic clarification that may aid in early diagnosis, treatment, and prophylaxis through epigenetic approaches and breeding.

HLA-A, -C, -B, -DRB1, -DQA1, and -DQB1 Allele and Haplotype Repertoires in the Albanian Population from Kosovo

ABSTRACT To give new insight into the huge polymorphism of HLA system and supplement the existing data, an analysis of HLA alleles and HLA-A~C~B~DRB1~DQA1~DQB1 haplotype distribution in 124 Albanian individuals from Kosovo was performed. All samples were HLA-typed applying the polymerase chain reaction-sequence specific oligonucleotide probing (PCR-SSOP) method and all ambiguous HLA typing results were additionally confirmed by the standard PCR-Sequence Specific Primers (PCR-SSP) high-resolution protocol. Twenty-two HLA-A, 21 HLA-C, 37 HLA-B, 27 HLA-DRB1, 11 HLA-DQA1 and 14 HLA-DQB1 allele groups were detected. Sixteen out of 172 different six-locus estimated haplotypes were found at a frequency higher than 1.00% with a cumulative frequency of 28.82%. The most prevalent haplotype was found to be HLA-A*02:01~C*07:01~B*18:01~DRB1*11:04~DQA1*05:05~DQB1*03:0(5.2%).A total of 13 haplotypes were observed with higher frequency than in populations reported in HaploStats and The Allele Frequency Net Database. The proposed origin of the most frequent haplotypes reflects a basic Euro-Mediterranean background of Albanians in Kosovo. This is the first report of high-resolution HLA-A~C~B~DRB1~DQA1~DQB1 haplotype distribution among the Albanian population from Kosovo, which provides valuable anthropological data and confirms population-specific characteristics.

HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 Allele and Haplotype Frequencies of 28,927 Saudi Stem Cell Donors Typed by Next-Generation Sequencing.

Human leukocyte antigen (HLA) allele and haplotype frequency distribution varies widely between different ethnicities and geographical areas. Matching for HLA alleles is essential for successful related and unrelated stem cell transplantation. Among the Saudi population, data on HLA alleles and haplotypes are limited. A cross-sectional study was performed on 28,927 bone marrow donors. The most frequent HLA alleles were HLA-A*02:01:01G (20.2%), A*24:02:01G (7.5%); B*51:01:01G (19.0%), B*50:01:01G (12.3%); C*06:02:01G (16.7%), C*07:02:01G (12.2%); DRB1*07:01:01 (15.7%), DRB1*03:01:01G (13.3%); DQB1*02:01:01G (29.9%), DQB1*03:02:01G (13.2%); and DPB1*04:01:01G (35.2%), DPB1*02:01:02G (21.8%). The most frequent HLA-A~C~B~DRB1~DQB1 haplotypes were A*02:01:01G~C*06:02:01G~B*50:01:01G~DRB1*07:01:01G~DQB1*02:01:01G (1.9%) and A*02:05:01G~C*06:02:01G~B*50:01:01G~DRB1*07:01:01G~DQB1*02:01:01G (1.6%). The most frequent HLA-A~C~B~DRB1~DQB1~DPB1 haplotypes were A*02:01:01G~C*15:02:01G~B*51:01:01G~DRB1*04:02~DQB1*03:02:01G~DPB1*04:01:0G (1%) and A*02:01:01G~C*07:02:01G~B*07:02:01G~DRB1*15:01:01G~DQB1*06:02:01G~ DPB1*04:01:01G (0.9%). Based on these haplotype frequencies, we provide forecasts for the fraction of patients with full matching and single mismatched donors for 3 to 6 loci depending on the registry size. With one million donors, about 50% of the patients would find an 8/8 match and 90% a 7/8 match. These data are essential for registry planning, finding unrelated stem cell donors, population genetic studies, and HLA disease associations.