DQB1 Alleles Research Articles

Association of HLA-DRB1 and -DQB1 Alleles with Susceptibility to IgA Nephropathy in Korean Patients.

BackgroundAssociations between IgA nephropathy (IgAN) and HLA-DRB1 and -DQB1 alleles have been reported in several ethnic groups. We investigated the association of HLA-DRB1 and -DQB1 alleles with the predisposition for IgAN and disease progression to end-stage kidney disease (ESKD) in Korean patients.MethodsWe analyzed HLA-DRB1 and -DQB1 genotypes in 399 IgAN patients between January 2000 and January 2019 using a LIFECODES sequence-specific oligonucleotide (SSO) typing kit (Immucor, Stamford, CT, USA) or a LABType SSO Typing Test (One Lambda, Canoga Park, CA, USA). Alleles with a significant difference in two-digit resolution were further analyzed using in-house sequence-based typing and sequence-specific primer PCR. As controls, 613 healthy hematopoietic stem cell donors were included. Kidney survival was analyzed in 281 IgAN patients with available clinical and laboratory data using Cox regression analysis. Where needed, P-values were adjusted using Bonferroni correction.ResultsThe allele frequencies of HLA-DRB1*0405 (corrected P [Pc]<0.001), -DQB1*0401 (Pc=0.048), and -DQB1*0302 (Pc=0.021) were significantly higher in IgAN patients than in controls, whereas those of HLA-DRB1*0701, -DRB1*1501, -DQB1*0202, and -DQB1*0602 (Pc<0.001 for all) were significantly lower in IgAN patients than in controls. The allele frequency of HLA-DQB1*0503 (Pc=0.016) was significantly lower in the ESKD group than in the non-ESKD group; however, there was no significant difference for ESKD progression between these groups.ConclusionsWe report novel associations of HLA-DRB1*1501, DQB1*0202, -DQB1*0302, and -DQB1*0401 with IgAN. Further studies of HLA alleles associated with IgAN progression in a larger cohort and in various ethnic groups are needed.

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.

Immunogenetics of heteroclitic recognition of HLA-DQB1 55R eplet specificity by human alloantibody

Heteroclitic antibodies bind to a related antigen with higher affinity than to the immunizing antigen to which they were generated. This uncommon phenomenon is not well characterized for antibodies to HLA antigens. Here we analyzed allosera reactivity from two transplant recipients sensitized to mismatched donor alleles DQB1*06:01 and DQB1*06:02 respectively. Epitope analysis demonstrated the reactivity of both sera was restricted to DQB1*04, 05, and 06 alleles, with a specificity associated with the 55R eplet. Serum from one of these subjects (TE) was significantly more reactive with DQB1*04 alleles than the immunizing DQB1*06:01 or other alleles, a pattern not present in serum from the other patient. Antibody absorption/elution experiments using B cell lines expressing DQB1*06:01 or DQB1*04:02 alleles confirmed that the heteroclitic TE antibody eluted from cells carrying DQB1*06:01 was significantly more reactive with beads carrying the DQB1*04 alleles than with the DQB1*06 or other alleles. The significantly higher reactivity of the heteroclitic alloantibody with DQB1*04 specificity was explained structurally by variations of amino acid residues within 3.5 Å of 55R. These findings have important implications for the interpretation of DQ alloantibody cross-reactivity frequently observed in transplant recipients.

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide

AbstractHematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

Human Leukocyte Antigens -DQA1 and -DQB1 Alleles in Patients With Common Warts.

IntroductionThe human papillomavirus induces the formation of lesions in different epithelia. Several studies describe an association of class II human leukocyte antigen with genital lesions, implying that they could also be related to the presence of common warts. The goal of this work was to determine the frequency of human leukocyte antigens (HLA)-DQA1 and HLA-DQB1 in Mexicans with common warts.MethodsThirty-two patients with a diagnosis of common warts, without any other systemic disease, and 100 healthy subjects from the same geographic area were recruited. The second exon of the HLA-DQA1 and HLA-DQB1 loci was typed by dot-blot and chemiluminescence.ResultsAlleles DQA1*03:01:01 (P = 0.021) and DQB1*03:02 (P = 0.036) were associated with the presence of skin warts. DQA1*04:01-DQB1*04:02 (P = 0.009) and DQA1*03:01:01-DQB1*03:02 (P = 0.044) were the most frequent haplotypes in patients.ConclusionIn conclusion, the results of our study showed that the alleles DQA1 *03:01:01, DQB1*03:02, DQA1 *04:01, and DQB1*04:02 were associated with susceptibility to common warts, while DQA1*05:01 was significantly diminished in them. Consequently, the haplotypes DQA1*04:01-DQB1*04: 02 and DQA1*03:01:01-DQB1*03:02 were found to be associated with susceptibility, and DQA1*05:01-DQB1*03:01 increased significantly in controls. Therefore, the alleles of the DQA1 and DQB1 genes that are associated with susceptibility could be presenting human papillomavirus (HPV) peptides to T lymphocytes that activate a Th2-type response (anti-inflammatory cytokines), which allows the development of skin warts in this population.

Association of HLA–DRB1, DQA1 and DQB1 alleles and haplotype in Parkinson’s disease from South India

Parkinson’s disease (PD) is a chronic, neurodegenerative motor disease exhibiting familial and sporadic forms. The present study was aimed to elucidate the association of HLA-DRB1*, DQA1* and DQB1* alleles with PD. A total of 105 PD patients and 100 healthy controls were typed by PCR-SSP method. We further carried out high-resolution genotyping for DQB1 and DQA1. Results revealed the increased frequencies of alleles DRB1*04 (OR = 2.36), DRB1* 13 (OR = 4.04), DQA1* 01:04:01 (OR = 4.51), DQB1*02:01 (OR = 2.66) and DQB1*06:03 (OR = 2.65) in PD patients suggesting susceptible associations. Further, decreased frequencies observed for alleles DRB1*10 (OR = 0.34), DRB1*15 (OR = 0.44), DQA1*04:01 (OR = 0.28), DQA1*06:01 (OR = 0.11) and HLA-DQB1*05:01 (OR = 0.37) among patients have suggested protective associations. Significant disease associations were observed for two-locus haplotype such as DRB1*13-DQB1*06:03 (OR = 11.52), DQA1*01:041-DQB1*06:03 (OR = 16.50), DQA1*01:041-DQB1*05:02 (OR = 5.38) and DQA1*04:01-DQB1*06:03 (OR = 3.027). Protective associations were observed for haplotypes DRB1*10-DQB1*05:01 (OR = 0.21), DRB1*15-DQB1*06 (OR = 0.006), DQA1*04:01-DQB1*05:01 (OR = 0.400) and DQA1*04:01-DQB1*05:03 (OR = 0.196). The critical amino acid residue analyses have revealed strong susceptible association for the residues of DQB1 alleles such as: L26, S28, K71, T71 and A74, Y9, S30, D37, I37, A38, A57 and S57; and for the residues of DQA1 alleles such as: C11, F61, I74, and M76. Similarly, amino acid residues such as A13, G26, Y26, A71, S74, L9 and V38 of HLA-DQB1 alleles and residues such as Y11, G61, S74 and L76 of DQA1 alleles showed protective associations. Thus, our study documented the susceptible and protective associations of DRB1*, DQB1 and DQA1 alleles and haplotypes in developing the disease and their influence on longevity of PD patients in south India.

Narcolepsy genetic marker HLA DQB1*06:02 and excessive daytime sleepiness in Parkinson disease patients treated with dopaminergic agents.

To determine whether narcolepsy Human Leukocyte Antigen (HLA) risk allele DQB1*0602 is associated with excessive daytime sleepiness (EDS) and inappropriate sleep in patients with Parkinson disease (PD). EDS is a common and disabling non-motor manifestation of PD, affecting quality of life and driving performance. DQB1*0602 is an HLA risk allele for narcolepsy. It is present in 12-30% of the general population. We hypothesize that DQB1*0602 is associated with an increased risk of EDS and inappropriate sleep in PD patients. This was a cross-sectional observational study of 150 PD individuals on dopaminergic agents. Main outcome measures were DQB1*0602 status and the modified Epworth Sleepiness Scale. Individuals with dementia, loss of independence, narcolepsy and untreated sleep apnea were excluded. Confounding variables for EDS were assessed using Parkinson Disease Sleep Scale, Mayo Sleep Questionnaire, Unified PD Rating Scale, Hoehn and Yahr scale. DQB1*06:02 positive PD patients were approximately three times more likely to experience EDS and fall asleep inappropriately during activities that required sustained alertness (e.g. driving, eating, attending work etc.). Exploratory post hoc analysis showed a dopaminergic drug dose- and type- dependent effect on daytime sleepiness in DQB1*06:02 positive individuals. No significant differences were found in confounding variables. PD individuals are more likely to experience EDS and fall asleep inappropriately during activities if DQB1*0602 positive. Genetic vulnerability may explain EDS risk in PD.

Association of HLA-DPA1, HLA-DPB1, and HLA-DQB1 Alleles With the Long-Term and Booster Immune Responses of Young Adults Vaccinated Against the Hepatitis B Virus as Neonates.

The neonatal hepatitis B vaccination (HBVac) was implemented 35 years ago in Taiwan, but many vaccinees exhibit inadequate long-term vaccine-induced seroprotective hepatitis B surface antibody (anti-HBs) levels. We investigated the association of the human leukocyte antigen (HLA) alleles (DPA1, DPB1, DQA1, and DQB1) with the long-term immunological response to the neonatal HBVac and adolescent booster HBVac in a Taiwanese cohort. We divided 281 Han students (median age 22, age range 17–29 years) into the following groups: (1) Group A (n = 61): anti-HBs titer ≥ 10 mIU/mL at the beginning of the study; (2) Group B (n = 75): anti-HBs level > 1000 mIU/mL after the first booster; (3) Group C (n = 37): anti-HBs level < 10 mIU/mL after the first booster; and (4) Group D (n = 5): anti-HBs level < 10 mIU/mL after three boosters. DQA1, DQB1, DPA1, and DPB1 typing of the participants was performed using sequence-specific oligonucleotides. Associations of HLA alleles and haplotypes with effects on neonatal HBVac and booster HBVac were examined through logistic regression analysis and Fisher’s exact test. A false discovery rate-based measure of significance, the q-value, was used for multiple comparisons, and an association was considered significant if the corresponding q-value was < 0.1. DPA1 alleles were associated with the long-term immunological response to the neonatal HBVac. The estimated odds ratio (OR) of the lack of HBV protective immunity when carrying an additional DPA1*01 and DPA1*02 was 0.36 [95% confidence interval (CI) = 0.17–0.76, p = 0.0076] and 2.39 (95% CI = 1.17–4.87, p = 0.016), respectively. DPB1 and DQB1 alleles were associated with a response to the adolescent booster vaccination. The estimated ORs of being nonresponsive to the first booster when carrying an additional DPB1*05 and DQB1*02 were 2.11 (95% CI = 1.13–3.93, p = 0.019) and 3.73 (95% CI = 1.43–9.71, p = 0.0070), respectively. All DPB1*03 carriers responded to the first booster (p of Fisher’s exact test = 0.0045). In our study, we discovered that HLA-DPA1 was primarily associated with the long-term response of primary infantile HBVac, and HLA-DPB1 and HLA-DQB1 exhibited associations with the HBV booster vaccination.

HLA-DRB1 and DQB1 genetic susceptibility to pemphigus vulgaris and pemphigus foliaceus in Vietnamese patients

Pemphigus is a group of rare, lifethreatening bullous autoimmune diseases that affect the skin and mucous membranes and are associated with high morbidity and morbidity. HLA class II genes, particularly HLA-DRB1 and HLA-DQB1, play roles in pemphigus. The aim of this paper is to investigate the susceptibility of HLA class II DRB1 and DQB1 alleles in Vietnamese patients with pemphigus vulgaris (PV) or pemphigus foliaceus (PF). The study enrolled 31 participants (22 with PV, 9 with PF) with diagnoses confirmed by clinical manifestations, histopathology, and direct immunofluorescence from November 2019 to June 2020. The HLA polymorphisms were determined by Sanger sequencing. The HLA-DRB1 and HLA-DQB1 profiles of the 101 healthy individuals in the control group have been published previously. The frequencies of HLA-DRB1*14, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were significantly higher, whereas those of DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 were significantly lower, in the PV group than in the controls. The frequencies of DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 were significantly higher in the PF group than in the controls. Alleles HLA-DRB1*14:54, DRB1*14:04, DRB1*14:03, DRB1*14:01, DRB1*14:12, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were associated with an increased risk of PV, whereas alleles DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 might protect against PV. In PF, DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 are promising susceptibility alleles.

HLA-DRB1*04 may predict the severity of disease in a group of Iranian COVID-19 patients

Human leukocyte antigen (HLA) genes with extreme diversity can make a contribution for individual variations to the immune response against SARS-COV-2 infection. This study aimed to explore the distributions of HLA class II alleles frequencies and their relations with disease severity in a group of Iranian COVID-19 patients. This prospective and case-control study was conducted on 144 COVID-19 patients including 46 cases with moderate form, 54 cases with severe and 44 cases with critical disease. HLA-DRB1 and -DQB1 allele families were determined by PCR-SSP method and compared between three groups of the patients and in comparison to 153 ethnic-matched healthy controls. The patients group showed lower frequencies of HLA-DRB1*15 (OR = 0.57, P = 0.06), DRB1*15 ~ DQB1*05 haplotype (P = 0.04) and DRB1*15/DRB1*04 genotype (P = 0.04) in compare with healthy controls. Moderate COVID-19 patients had higher frequencies of HLA-DRB1*04 (P = 0.03), HLA-DRB1*10 (P = 0.05) and DRB1*04/DRB1*11 genotype (P = 0.01). Also, a higher significantly frequency of HLA-DRB1*03 allele group was observed in the critical patients versus controls (P = 0.01). Multiple logistic regression analysis revealed that the presence of DRB1*04 allele group was negatively associated with development of severe and critical disease (OR: 0.289, P = 0.005). Our results indicate a possible contribution of some HLA class II alleles in disease severity and clinical features of COVID-19 disease.

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.

Probability of Finding a Matched Unrelated Donor for An Asian Indian Patient Who Needs a Stem Cell Transplant.

Abstract 4343In March 2008 we initiated a matched unrelated donor (MUD) bone marrow transplant program. Forty three searches have been performed through the National Marrow Donor Program USA (NMDP) and through the German Registry (DKMS) and completed data is available on 17 patients. High resolution HLA typing for A, B, DRB1, C and DQB1 alleles was done by Histogenetics (USA), NMDP or DKMS. Of the 17 patients for whom the search process was completed we identified a 10/10 matched donor for 7 patients, a 9/10 for 7 patients and an 8/10 for one patient. The 8/10 mismatch was at the C and DQB1 loci. Thus 15 of 17 (88%) had a suitable donor identified. After the preliminary search 2 patients were unlikely to have a donor. Of the15 matched donors, 4 were Caucasian and 11 were Asian. HLA is determined by the racial background of the individual and therefore the probability of finding a high resolution allele matched donor for an Asian Indian would have been low in registries that are predominantly Caucasian. Identification of matches from among the primarily Caucasian donor pool is interesting and may reflect a Caucasoid background in some of the population in the sub continent. In 11 out of the 17 completed searches an Asian donor was identified (61%). The NMDP has 7.5 million donors of which 553,000 are Asian and Pacific Islanders, 141,462 are South Asian, and 36,790 are Southeast Asian. These data exclude Asian donors reported as being from multiple races. Thus there was a 61% probability of finding a matched donor from among the 141,462 South Asian donors registered with the NMDP.Eleven patients have had a MUD transplant (Acute Myeloid Leukemia: 8, Acute Lymphatic Leukemia: 2 and Myelofibrosis: 1): 3 patients died before engraftment, 8 engrafted, 5 remain in remission, 2 have relapsed and one died of sepsis 100 days post transplant. The remaining four patients with matched donors are awaiting transplant.Since identification of a well-matched donor (allele matched at HLA-A, B, C, DRB1) is important for good outcome after MUD transplantation, these early search data for Indian patients suggest the need for a greater number of donors in India to be available and HLA typed in order to increase the probability of finding a suitable match for patients needing a MUD transplant.Number of SearchesDonor 10/10Donor 9/10Donor 8/10No DonorDonor M/FDonor C/ADonor CMV +/-/?Matched donor able to proceed to collection Yes/NoTransplanted187 [39%]7 [39%]1 [6%]3 [17%]12/34/119/5/411/411C- Caucasian A- Asian Disclosures:No relevant conflicts of interest to declare.

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.

Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population.

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.

Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity.

We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children's Research Hospital's Total XVI (TXVI, n=598) and Children's Oncology Group AALL0232 (n=2,472) and AALL0434 (n=1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P=2.7×10-5 in TXVI) and male sex (P=0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P<5.0×10-5 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r2 =0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P=8.9×10-9 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.

Immunogenetic characteristics of potential donors of hemapoietic stem cells recruited in the North Caucasus

Aim of the study was to investigate the immunogenetic characteristics of the potential donors of hematopoietic stem cells recruited in the North Caucasus and the distribution features of HLA alleles and multilocus haplotypes. Material and methods . Next Generation Sequencing technology was used to identify HLA-A, -B, -C, -DRB1 and -DQB1 alleles from 2663 unrelated bone marrow volunteers living in the Chechen Republic, Stavropol region, Republic of Dagestan. Mass parallel sequencing was performed using the MiSeq™ System («Illumina Inc.», USA). HLA allele and haplotype frequencies were estimated via maximum-likelihood analysis from genotypic data through an expectationmaximization (EM) algorithm for unknown gametic phase using Arlequin v. 3.5.2.2. Results and discussion . In studied population, 47 HLA-A, 77 HLA-B, 39 HLA-C, 54 HLA-DRB1, 22 HLA-DQB1 alleles were selected. Thirteenth alleles, HLA-A*02:01, HLA-A*01:01, HLA-B*13:02, HLA-B*51:01, HLA-C*06:02, HLA-C*04:01, HLA-C*07:02, HLADRB1*07:01, HLA-DRB1*13:01, HLA-DQB1*03:01, HLA-DQB1*02:02, HLA-DQB1*06:03, DQB1*03:02 exhibit frequencies over 10 %. The highest frequency extended haplotype HLA-A*02:01-B*13:02-C*06:02-DRB1*07:01DQB1*02:02, was observed frequencies of 4,5 %. Routine HLA typing allowed us to define 13 new HLA alleles.

Clinical Relevance of HLA-DRB1 and -DQB1 Alleles in Iranian Systemic Lupus Erythematosus Patients.

Given the potential link between genetic risk factors and clinical features of systemic lupus erythematosus (SLE), this study aimed to explore the relationship between human leukocyte antigen (HLA)-DRB1/DQB1 alleles and haplotypes and clinical sub-phenotypes of the disease in a group of Iranian SLE patients. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSP in 127 SLE patients and 153 ethnically-matched healthy controls. The relationships between various clinical manifestations and HLA alleles/haplotypes were analyzed in the patients. We observed the positive associations of DRB1*07 and DRB1*07-DQB1*02 haplotypes with articular and pulmonary involvement (p=0.006 and p<0.001 respectively), DRB1*03 and DQB1*02 alleles, and DRB1*03-DQB1*02 haplotypes with cutaneous (p=0.03, p=0.004 and p=0.02 respectively) and renal involvement, and DRB1*13 as well as DRB1*13-DQB1*06 haplotypes with renal involvement. Conversely, negative associations of DRB1*13 with cutaneous and gastrointestinal disorders (p=0.004 and p=0.02 respectively) and DRB1*01 with renal involvement (p=0.03) were found in our patients. Patients carrying susceptible HLA-DRB1 alleles had a higher risk for expression of cutaneous involvement (p=0.03), anti-coagulant antibody development (p=0.01), and a lower risk for pulmonary disorders compared to patients' negatives for susceptible alleles (p=0.04). Our findings on associations between HLA risk allele (DRB1*03) as well as non-risk alleles with particular clinical manifestations and between the potentially protective allele (DRB1*01) and protection against renal involvement indicate the important role of HLA class II genes in predisposing of specific serological and clinical features of SLE disease which could be implicative for therapeutic applications and better management of SLE patients.

Distribution of HLA-DQA1, -DQB1 and -DRB1 genes and haplotypes in Han, Uyghur, Kazakh and Hui populations inhabiting Xinjiang Uyghur Autonomous Region, China.

Genetic polymorphisms of human leucocyte antigen (HLA)-DRB1, -DQA1 and -DQB1 among four main ethnic groups including Han (n=70), Uyghur (n=71), Kazakh (n=52) and Hui (n=40) subjects from Xinjiang Uyghur Autonomous Region were investigated using a polymerase chain reaction-sequence-based typing (PCR-SBT). In total, 32 HLA-DRB1 alleles, eight HLA-DQA1 alleles and 14 HLA-DQB1 alleles were identified. The most predominant HLA-DRB1, -DQA1 and -DQB1 alleles were DRB1*15:01 (12.50%), DQA1*01:02 (21.43%) and DQB1*03:01 (19.29%) in Han; DRB1*07:01 (18.48%), DQA1*05:01/03/05 (24.65%) and DQB1*02:01/02 (31.69%) in Uyghur; and DRB1*13:01 (13.64%), DQA1*05:01/03/05 (28.85%) and DQB1*02:01/02 (27.88%) in Kazakh, respectively. In Hui, DRB1*07:01, DRB1*11:01 and DRB1*14:01 were the most dominant alleles with the same frequency of 11.8%, while the predominant DQA1 and DQB1 alleles were DQA1*03:01/02/03 (23.75%) and DQB1*02:01/02 (16.25%), respectively. In addition, the most common two-locus haplotypes were DQA1*05:01/03/5-DQB1*03:01 (10.0%) in Han; DQA1*02:01-DQB1*02:01/02 (18.31%) in Uyghur; DQA1*05:01/03/05-DQB1*02:01/02 (15.38%) in Kazakh; and DQA1*03:01/02/03-DQB1*03:03 (11.25%) in Hui. The phylogenetic dendrograms constructed based on the allele frequencies of HLA-DRB1, -DQA1 and -DQB1 in 13 populations (e.g. Asian, Central Asian and European) revealed that the Han and Hui populations were clustered together and closest to Han population from China, while the Kazakh and Uyghur populations were closest to each other and two ethnic groups were clustered together with Central Asian and European populations.

HLA Class II alleles and association with HPV Infection prevalence in high-risk HPV-positive Han women in southern China

ObjectiveTo investigate the prevalence of different human papillomavirus (HPV) subtypes and their association with human leukocyte antigen (HLA) class II alleles in China. Patients and methodsA total of 16,168 married Chinese women in Maoming City of Guangdong province were tested for high-risk HPV infection. High-resolution typing of HLA-DRB1/DQB1 alleles was also performed on samples found to be infected with HPV. ResultsAll in all, HPV-52, −58, −16, −18, and −53 were the five most common subtypes of HPV, with an incidence of high-risk HPV infection of 7.14%. Among women at high-risk of HPV infection, −DRB1*0403 (3.12% vs. 1.67%, odds ratio [OR] 1.894), −DQB1*0602 (3.74% vs. 1.82%, OR 2.094), and −DQB1*0609 (2.02% vs. 0.91%, OR 2.249) frequencies were higher than in controls. In contrast, −DQB1*0402 (0.31% vs. 1.29%, OR 0.239) in women with high-risk HPV infection exhibited a significantly decreased frequency compared to the controls. ConclusionOur results strongly support previous findings from other populations that −DRB1*0403 and −DQB1*0602 may be risk factors for HPV infection and subsequent development of cervical cancer. Moreover, unlike the European population, −DQB1*0402 may protect rather than render Maoming women susceptible to HPV infection.