Distribution Of HLA Alleles Research Articles

HLA-A, -B, -C and -DRB1 Association with Autism Spectrum Disorder Risk: A Sex-Related Analysis in Italian ASD Children and Their Siblings.

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to "compensatory skills" in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

Telomere Length, HLA, and Longevity-Results from a Multicenter Study.

Aging is an exceptionally complex process that depends on genetic, environmental, and lifestyle factors. Previous studies within the International HLA and Immunogenetics Workshop (IHIWS) component "Immunogenetics of Ageing" showed that longevity is associated with positive selection of HLA-DRB1*11- and DRB1*16-associated haplotypes, shown to be protective against diseases. Within the 18th IHIWS, we aimed to investigate the relevance of telomere length for successful aging and its association with classical HLAs. In total 957 individuals from Bulgaria, Turkey, Romania, and Poland in two age groups, elderly individuals (age 65-99 years) and ethnically matched young group (age 18-64 years), were investigated. The obtained results confirmed interpopulation differences in the distribution of HLA alleles, documented the lengths of telomeres in analyzed populations, and demonstrated significant associations of telomere length with aging as well as with the presence of some HLA class I or class II alleles. They suggest that telomere length assessment combined with HLA genotyping may help identify immunogenetic profiles associated with longevity. The associations between HLA and telomeres support the theory that HLA genes influence the aging process. However, further research is needed to clarify the biological basis of the observed relationships.

HLA Association among Thai Patients with Diffuse and Limited Cutaneous Systemic Sclerosis.

This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the Next Generation DNA Sequencing method (three fields) in 92 Thai patients with systemic sclerosis (55 dcSSc, 37 lcSSc) and 135 healthy controls (HCs). The distribution of HLA alleles in patients with dcSSc and lcSSc was compared. When compared with HCs, the AF of A*24:02:01, A*24:07:01, B*27:04:01 and B*27:06 showed an increasing trend in lcSSc patients without statistical significance. DRB1*15:02:01, DRB5*01:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01 increased significantly in dcSSc patients. DQB1*05:01:24 and DPB1*13:01:01 also increased significantly in lcSSc patients, but less significantly than in dcSSc patients. The association of DPB1*05:01:01 with lcSSc was significantly protective. HLA-A*24:02:01, B*27:06 and C*03:04:01 formed a three-locus haplotype that also constituted an eight-locus haplotype with DRB1*15:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01. There was a possibility that HLA Class I would play a role in the pathogenesis of lcSSc, while Class II played more of a role in the dcSSc in Thai patients.

Low C4A copy numbers and higher HERV gene insertion contributes to increased risk of SLE, with absence of association with disease phenotype and disease activity.

Low copy numbers (CNs) of C4 genes are associated with systemic autoimmune disorders and affects autoantibody diversity and disease subgroups. The primary objective of this study was to characterize diversity of complement (C4) and C4-Human Endogenous Retrovirus (HERV) gene copy numbers in SLE. We also sought to assess the association of C4 and C4-HERV CNs with serum complement levels, autoantibodies, disease phenotypes and activity. Finally, we checked the association of C4 and HERV CNs with specific HLA alleles. Genomic DNA from 70 SLE and 90 healthy controls of south Indian Tamil origin were included. Demographic, clinical and serological data was collected in a predetermined proforma. CNs of C4A and C4B genes and the frequency of insertion of 6.4kb HERV within C4 gene (C4AL, C4BL) was determined using droplet digital polymerase chain reaction (ddPCR). A four digit high resolution HLA genotyping was done using next generation sequencing. In our cohort, the total C4 gene copies ranged from 2 to 6. Compared to controls, presence of two or less copies of C4A gene was associated with SLE risk (p = 0.005; OR = 2.79; 95% CI = 1.29-6.22). Higher frequency of HERV insertion in C4A than in C4B increases such risk (p = 0.000; OR = 12.67; 95% CI = 2.80-115.3). AL-AL-AL-BS genotype was significantly higher in controls than SLE (9%vs1%, p = 0.04; OR = 0.15, 95% CI = 0.00-0.16). Distribution of HLA alleles was not different in SLE compared to controls as well as in SLE subjects with ≤ 2 copies and > 2 copies of C4A, but HLA allele distribution was diverse in subjects with C4B ≤ 2 copies and > 2 copies. Finally, there was no correlation between the C4 and the C4-HERV diversity and complement levels, autoantibodies, disease phenotypes and activity. In conclusion, our data show that, low C4A copy number and higher insertion of HERV-K in C4A increases the risk for SLE. C4 and C4-HERV CNs did not correlate with serum complements, autoantibodies, disease phenotypes and activity in SLE. Further validation in a larger homogenous SLE cohort is needed.

An Optimal Multi-Locus HLA-Typing in Potential Donors of Allogeneic Hematopoietic Stem Cells

Background. HLA-typing and matched donor selection as well as the detection of donor-specific anti-HLA antibodies are essential for allogeneic hematopoietic cell transplantation (allo-HSCT). In accordance with the guidelines of the Center for International Blood and Marrow Transplant Research (CIBMTR) optimal HLA-typing is performed on 11 HLA genes (-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1) with an adequate coverage aiming to obtain the values at the two-field level.
 Aim. To assess the results of multi-locus HLA-typing in bone marrow/hematopoietic cell donors from the database at the National Research Center for Hematology in terms of their conformance with the CIBMTR guidelines for allo-HSCT and to analyze the frequency and distribution of HLA alleles and multi-locus HLA haplotypes.
 Materials & Methods. The study enrolled 3485 donors who were HLA-typed by next-generation sequencing.
 Results. In all donors, the alleles of HLA class I genes were identified at the fourth-field level (nucleotide sequence). When the results were reduced to the second-field level (amino acid sequence), 61 HLA-A, 92 HLA-B, and 49 HLA-C alleles were detected. The alleles of class II genes were discovered either at the two-field or high-resolution levels. Among the HLA-DRB locus genes, 57 DRB1, 11 DRB3, 6 DRB4, and 5 DRB5 alleles were identified. Also, 23 HLA-DQA1, 30 HLA-DQB1, 14 HLA-DPA1, and 33 HLA-DPB1 alleles were detected. There were reported 3289 different HLA haplotypes of A-B-C-DRB1-DQA1-DQB1-DPA1-DPB1 genes.
 Conclusion. The database created at the National Research Center for Hematology includes potential bone marrow/hematopoietic stem cell donors typed for 11 classical polymorphic genes HLA-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and -DPB1, which is in line with the guidelines of CIBMTR. The frequency and distribution of HLA alleles and multi-locus HLA haplotypes in our donors correspond to those in populations of European origin. HLA-typing and donor selection with regard to 11 HLA genes will contribute to improving the outcomes of both unrelated and haploidentical HSCTs.

An intermediate-sized donor registry experience: HLA barriers in matching procedures.

The data enabling the estimation of the possibility of finding a matched unrelated donor (MUD) within a relatively short time is important for the success of hematopoietic stem cell transplantation (HSCT). In the present study, 738 unrelated Croatian patients in the program of unrelated HSCT were retrospectively analyzed for gender matching, donor origin (national or international), the distribution of HLA alleles and haplotypes, as well as for the probability of finding a 9-10/10 MUD. Almost 70% of the patients in our study group had a 10/10 MUD, while among the patients with a 9/10 MUD, a 1st field resolution level mismatched donor was selected for 55.0% of patients. The majority of pairs were HLA-A mismatched (33.8%). A comparison of HLA allele frequencies between two subgroups of patients revealed significant differences for 13 alleles. However, after p value correction, the difference in frequency remained significant only for four alleles; three HLA alleles (B*08:01, C*07:01, and DRB1*03:01) demonstrated a significantly higher frequency among patients with a 10/10 MUD (Pcorr < 0.0001, Pcorr = 0.0096, and Pcorr < 0.0001, respectively), while the B*35:08 allele was significantly more present among patients with a 9/10 MUD (Pcorr = 0.0328). The comparison of the distribution of HLA haplotypes between patients with a 10/10 MUD and patients with a 9/10 MUD showed significant differences for a number of two-locus and three-locus haplotypes, as well as for one five-locus haplotype (HLA-A*01:01~B*08:01~C*07:01~DRB1*03:01~DQB1*02:01), which was significantly more present in the group of patients with a 10/10 MUD. At least one HLA haplotype from the group of non-frequent HLA haplotypes (positions >1000) was carried by patients with a 9/10 MUD. The data obtained by the present study will contribute to a better estimation of the probability of finding a suitable 9-10/10 MUD for Croatian patients in need of HSCT.

Impact of predicted HLA class I immunopeptidome on viral reservoir in a cohort of people living with HIV in Italy.

The class I HLA genotype has been widely recognized as a factor influencing HIV disease progression in treatment-naïve subjects. However, little is known regarding its role in HIV disease course and how it influences the size of the viral reservoir once anti-retroviral therapy (ART) is started. Here, leveraging on cutting-edge bioinformatic tools, we explored the relationship between HLA class I and the HIV reservoir in a cohort of 90 people living with HIV (PLWH) undergoing ART and who achieved viral suppression. Analysis of HLA allele distribution among patients with high and low HIV reservoir allowed us to document a predominant role of HLA-B and -C genes in regulating the size of HIV reservoir. We then focused on the analysis of HIV antigen (Ag) repertoire, by investigating immunogenetic parameters such as the degree of homozygosity, HLA evolutionary distance and Ag load. In particular, we used two different bioinformatic algorithms, NetMHCpan and MixMHCpred, to predict HLA presentation of immunogenic HIV-derived peptides and identified HLA-B*57:01 and HLA-B*58:01 among the highest ranking HLAs in terms of total load, suggesting that their previously reported protective role against HIV disease progression might be linked to a more effective viral recognition and presentation to Cytotoxic T lymphocytes (CTLs). Further, we speculated that some peptide-HLA complexes, including those produced by the interaction between HLA-B*27 and the HIV Gag protein, might be particularly relevant for the efficient regulation of HIV replication and containment of the HIV reservoir. Last, we provide evidence of a possible synergistic effect between the CCR5 ∆32 mutation and Ag load in controlling HIV reservoir.

Role of Human Leukocyte Antigen Class II in Antibody-Mediated Skin Disorders.

HLA class II molecules are key factors determining susceptibility to autoimmune disorders, and their role in immune-mediated skin conditions such as psoriasis has been extensively investigated. However, there is currently little understanding of their role in antibody-mediated skin diseases such as autoimmune blistering disorders. We researched the available literature using PubMed to narratively review the current knowledge on HLA associations in antibody-mediated blistering skin pathologies. Our results summarized the risk alleles that are identified in the literature, together with certain known protective alleles: in the pemphigus group, alleles HLA-DQB1*0503 and HLA-DRB1*0402 are most commonly associated with disease; in the pemphigoid group, the most studied allele is HLA-DQB1*0301; in epidermolysis bullosa acquisita, few genetic studies are available; in dermatitis herpetiformis, the association with haplotypes HLA-DQ2 and HLA-DQ8 is strongly established; finally, in linear IgA bullous disease, specific HLA alleles may be responsible for pediatric presentations. Our current pathogenic understanding of this group of disorders assigns a key role to predisposing HLA class II alleles that are able to bind disease autoantigens and therefore stimulate antigen-specific autoreactive T cells. The latter engage B lymphocytes that will produce pathogenic autoantibodies. The distribution of HLA alleles and their disease associations are variable across demographics, and an in-depth pathogenetic understanding is needed to support associations between HLA alleles and disease phenotypes. Additionally, in a personalized medicine approach, the identification of HLA alleles associated with the risk of disease may become clinically relevant in identifying susceptible subjects that should avoid exposure to known triggers, such as medication, when possible.

Population genetics and external proficiency testing for HLA disease associations.

Numerous associations of HLA variants with susceptibility to diseases, namely, those with an immunopathological component, have been described to date. The strongest HLA associations were incorporated into the standard algorithms for the diagnostics. Disease-associated HLA variants are routinely detected by various techniques including DNA-based assays. For the identification of HLA markers or their combinations with the highest diagnostic value and those with frequent clinical indications (e.g., HLA-B*27, -B*57:01, -DQ2/-DQ8, -DQB1*06:02), diagnostic tests that focus on a single or limited number of specific HLA antigens/alleles, have already been developed; the use of complete typing for particular HLA loci is a relevant alternative. Importantly, external proficiency testing (EPT) became an integral part of good laboratory practice for HLA disease associations in accredited laboratories and not only supports correct "technical" identification of the associated HLA variants, but also adequate interpretation of the results to the clinicians. In the present article selected aspects of EPT for HLA disease associations related to population genetics are reviewed and discussed with the emphasis on the optimal level of HLA typing resolution, population-based differences in disease associated HLA alleles within the allelic group, distribution and linkage disequilibrium of HLA alleles in particular populations and interpretation of the presence of less common HLA variants/haplotypes. In conclusion, the laboratories that perform and interpret the tests to the clinicians, producers of the certified diagnostics and EPT providers should consider, among others, the genetic characteristics of the populations in order to optimise the diagnostic value of the tests for disease-associated HLA variants.

Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment.

Sarcoidosis is an immune-mediated systemic disease with unknown etiology affecting the lung predominantly. The clinical manifestation of sarcoidosis is rather diverse ranging from Löfgren's syndrome to fibrotic disease. Also, it differs among patients with distinct geographical and ethnic origins, consistent with environmental and genetic factors' role in its pathogenesis. Of those, the polymorphic genes of the HLA system have been previously implicated in sarcoidosis. Therefore, we have performed an association study in a well-defined cohort of Czech patients aiming to define how variation in HLA genes, may contribute to disease origin and development. Total of the 301 Czech unrelated sarcoidosis patients were diagnosed according to international guidelines. In those, HLA typing was performed using next-generation sequencing. The allele frequencies at six HLA loci (HLA-A,-B,-C,-DRB1,-DQA1, and -DQB1) observed in the patients were compared with HLA allele distribution determined in 309 unrelated healthy Czech subjects; sub-analyses of relationships between HLA and distinct sarcoidosis clinical phenotypes were performed. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. We report two variants, HLA-DQB1*06:02, and HLA-DQB1*06:04, as risk factors for sarcoidosis, and three variants, HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 as protective factors. HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DQA1*05:01, and HLA-DQB1*02:01 variants associated with Löfgren's syndrome, a more benign phenotype. HLA- DRB1*03:01 and HLA-DQA1*05:01 alleles were connected with better prognosis-chest X-ray (CXR) stage 1, disease remission, and non-requirement of corticosteroid treatment. The alleles HLA-DRB1*11:01 and HLA-DQA1*05:05 are associated with more advanced disease represented by the CXR stages 2-4. HLA-DQB1*05:03 associated with sarcoidosis extrapulmonary manifestation. In our Czech cohort, we document some associations between sarcoidosis and HLA previously described in other populations. Further, we suggest novel susceptibility factors for sarcoidosis, such as HLA-DQB1*06:04, and characterize associations between HLA and sarcoidosis clinical phenotypes in Czech patients. Our study also extends the role of the 8.1 ancestral haplotype (HLA-A*01:01∼HLA-B*08:01∼HLA-C*07:01∼HLA-DRB1*03:01∼HLA-DQA1*05:01∼HLA-DQB1*02:01), already implicated in autoimmune diseases, as a possible predictor of better prognosis in sarcoidosis. The general translational application of our newly reported findings for personalized patient care should be validated by an independent study from another, international referral center.

Problems of allogenic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for many malignant and non-malignant diseases of the blood system. With an existing need of five thousand HSCT per year, about two thousand are performed, therefore, not all those in need receive this type of treatment. The purpose of the study is to study the main problems of allogeneic hematopoietic stem cell transplantation, to identify risk factors, frequency of occurrence and impact on the outcome of allo-HSCT of key post-transplant complications. A large number of nationalities and ethnic groups live in the country, characterized by a unique distribution and frequency of HLA alleles, which led to the formation of a specific allelic polymorphism of HLA genes, characteristic only for residents of Russia. In this regard, about 25 % of patients do not have a compatible donor in the world. Graft failure is a group of complications characterized by two- or three-lineage cytopenia in combination with bone marrow hypo-/aplasia and is a major cause that impairs patients short-term survival rates after allo-HSCT and affects an average of 40 % of all recipients. The study confirms the need to replenish the Federal Register with new hematopoietic stem cell (HSC) donors, which will increase the likelihood of finding a compatible HSC donor for the recipient with a nondisseminated HLA genotype.

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.

Pattern of HLA types in renal transplant patients in Sohag Governorate

Objective This study aimed to assess the pattern of HLA types in Egyptian renal transplant patients in the Sohag governorate. Materials and methods A retrospective chart review was conducted on all patients and their donors, who were scheduled to undergo renal transplantation at Sohag University Hospital through the period from January 2010 to December 2019. We retrieved the following data from eligible patients’ files: age of the recipient and donor, gender of the recipient and donor, consanguinity, blood group, cross-matching, HLA classes A and B, and DR alleles. Results Overall, a total of 26 recipients (70.3%) and 25 donors (67.6%) had HLA-A alleles, while 22 recipients (59.5%) and 26 donors (70.3%) had HLA-B alleles. In terms of the pattern of HLA-A distribution among recipients, the most frequent alleles were A*01/02 (8.1%), A*02/23 (5.4%), A*02/32 (5.4%), and A*02 (5.4%). On the other hand, the most frequent HLA-A alleles in the donors’ group were A*01/02 (5.4%), A*02/03 (5.4%), and A*26/68 (5.4%). Regarding HLA-B allele distribution, all recipients had different alleles. While B*41/52 was the most frequent allele in the donors’ group. All recipients, except two patients, had HLA-DR alleles, most commonly DR*11/13 (13.5%) and DR*13/15 (8.1%). Negative cross-matching was present in 59.5% of the cases. Among female recipients, only A*13/15 and B*27/51/53 alleles were detected. Conclusion In conclusion, our findings were very similar to the results from other local and global studies. Different populations and ethnicities are the main dependent variables of the major differences in terms of HLA allele distribution.

Genetics: Is LADA just late onset type 1 diabetes?

BackgroundThere is a controversy regarding Latent Autoimmune Diabetes in Adults (LADA) classification and whether it should be considered a slowly progressing form of type 1 (T1) diabetes (DM) or a distinct type of DM altogether.MethodsThis cross-sectional study assessed major genes associated with T1DM (class II HLA, PTPN22 [rs2476601] and INS [rs689]) in patients with LADA, as compared with participants with T1DM (stratified according to age of diagnosis before or after 30) and T2DM. HLA genotyping of the DRB1, DQA1 and DQB1 loci was performed by reverse PCR sequence-specific oligonucleotides. HLA haplotypes were assigned according to those most frequently described in the European population. INS and PTPN22 SNPs were genotyped by real-time PCR.ResultsA total of 578 participants were included: 248 with T1DM (70 diagnosed after the age of 30), 256 with T2DM and 74 with LADA. High risk HLA alleles were significantly more frequent in LADA than in T2DM, whereas the opposite was true for protective alleles. We found a lower frequency of the high-risk DRB1*04-DQB1*03:02-DQA1*03:01 haplotype in LADA (21.1%) than in the overall T1DM (34.7%) (p<0.05), whereas no differences were found between these groups for DRB1*03-DQB1*02:01-DQA1*05:01 or for protective alleles. Only 12% the overall T1DM group had no risk alleles vs 30% of LADA (p<0.0005). However, HLA allele distribution was similar in LADA and T1DM diagnosed after the age of 30. A total of 506 individuals (195 with T1DM [21 diagnosed after age 30] 253 with T2DM and 58 with LADA) were genotyped for the PTPN22 and INS SNPs. The G/A genotype of the PTPN22 rs2476601 was more frequent and the T/T genotype of the INS SNP rs689 was less frequent in T1DM compared to LADA. We did not find any significant differences in the frequency of the mentioned SNPs between LADA and T2DM, or between LADA and T1DM diagnosed after the age of 30.ConclusionIn this relatively small cross-sectional study, the genetic profile of subjects with LADA showed a similar T1DM-related risk allele distribution as in participants with T1DM diagnosed after the age of 30, but fewer risk alleles than those diagnosed before 30. Differences were present for HLA, as well as PTPN22 and INS genes.

Significance of regional population HLA immunogenetic datasets in the efficacy of umbilical cord blood banks and marrow donor registries: a study of Cretan HLA genetic diversity

Background aimsThe high genetic diversity of HLA across populations significantly confines the effectiveness of a donor or umbilical cord blood search for allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to probe the HLA immunogenetic profile of the population of Crete, a Greek region with specific geographic and historical characteristics, and to investigate potential patterns in HLA distribution following comparison with the Deutsche Knochenmarkspenderdatei (DKMS) donor registry. It also aims to highlight the importance of regional public cord blood banks (PCBBs) in fulfilling HSCT needs, especially in countries with significant genetic diversity. MethodsA cohort of 1835 samples representative of the Cretan population was typed for HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1, HLA-DPB1) loci by high-resolution second field next-generation sequencing. Data were compared with the respective HLA profiles of 12 DKMS populations (n = 20 032). Advanced statistical and bioinformatics methods were employed to assess specific intra- and inter-population genetic indexes associated with the regional and geographic distribution of HLA alleles and haplotypes. ResultsA considerable HLA allelic and haplotypic diversity was identified among the Cretan samples and between the latter and the pooled DKMS cohort. Even though the HLA allele and haplotype frequency distribution was similar to regions of close geographic proximity to Crete, a clinal distribution pattern from the northern to southern regions was identified. Significant differences were also observed between Crete and the Greek population of DKMS. ConclusionsThis study provides an in-depth characterization of the HLA immunogenetic profile in Crete and reveals the importance of demographic history in HLA heterogeneity and donor selection. The novel HLA allele and haplotype frequency comparative data between the Cretan and other European populations signify the importance of regional PCBBs in prioritizing HLA diversity to efficiently promote the HSCT program at the national level and beyond.

HLA Alleles and Haplotypes Frequency in the Population of the Republic of Tatarstan, Russia

Inroduction HLA matching is essential for selection of the best matched tissue transplant donors. Only 30% of blood relatives are suitable to be the donor, making the need for non-relative matched donors a significant issue in transplantation. In response to an increased need for the HLA compatible donors of the hematopoietic stem cells, Kazan Federal University together with the «Rusfond» Charity established the «Rusfond. Register», a thoroughly characterized registry of the potential bone marrow donors. The goal of the «Rusfond. Register» is to create the regional register of the donors in the Republic of Tatarstan as a part of the National register of Russian Federation. Matherials and methods Blood samples from 483 potential bone marrow donors were collected. The Institutional Review Board of the Kazan Federal University approved this study and informed consent was obtained from each study subject according to the guidelines approved under this protocol (article 20, Federal Law “Protection of Health Rights of Citizens of Russian Federation” N323-FZ, 11.21.2011). DNA was extracted using «PROTRANS DNA Box 500» (PROTRANS, Germany) kit according to the manufacturer's instructions. Human leukocyte antigen (HLA) genotype was analyzed using SSP-PCR Cyclerplate System «PROTRANS HLA-A*/B*/Cw*» and «PROTRANS HLA-DRB1*/DQB1*» according to the manufacturer's protocols. Allele frequencies and genotypes for five HLA-loci were calculated. Haplotype frequencies were determined by expectation maximization algorithm and the Hardy-Weinberg equilibrium verification was carried out using Arlequin ver. 3.5 software (Excoffier et al, 2005). Results and discussion Five HLA-loci genotypes (HLA-A, -B, -C, -DRB1, and -DQB1) were examined, where there number of each allele families was as follows: 18 - A*, 27 - B*, 14 - C*, 13 - DRB1* and 5 - DQB1*. However, rare alleles (A*74, A*80, B*59, B*67, B*73, B*78), previously reported in Russia were not detected. The highest frequency alleles were: A* - А*02 (30.12%), А*03 (14.39%), А*24 (11.80%), A*01 (11.59%); B* - B*35 (12.53%), B*07 (10.46%), B*44 (8.90%); C* - C*07 (26.29%), C*04 (14.08%), C*06 (11.90%), C*12 (11.59%), C*03 (9.73%); DRB1* - DRB1*07 (14.91%), DRB1*13 (13.77%), DRB1*15 (13.77%), DRB1*11 (12.63%), DRB1*01 (11.59%), DRB1*04 (10.77%) and DQB1* - DQB1*03 (34.78%) (Fig. 1). Allele frequency among bone marrow donors in the Republic of Tatarstan was similar to that observed in different Caucasian populations (Novac et al, 2008; Lima et al, 2013). Interestingly, low frequency of alleles specific for Mongoloids was found within the bone marrow donors in Republic of Tatarstan. Also, the frequency of haplotypes was examined. Among three-locus HLA-A-B-DRB1, the highest frequency was A*03-B*35-DRB1*01 haplotype (3.33%), followed by A*01-B*08-DRB1*03 (2.80%), A*02-B*13-DRB1*07 (2.26%) and A*24-B*07-DRB1*15 (2.04%). The frequency of these haplotypes closely resembles those observed within the Russian and Tatar populations in Chelyabinsk Region of Russia (Suslova et al, 2012). Conclusion Our data suggests that HLA-allele and haplotype profiles of bone marrow donors in the Republic of Tatarstan are closely resemble the Caucasian profile. Obtained data will be useful for the analysis of HLA-allele distribution in the Republic of Tatarstan and Russia as well as for the optimization of an initial screening for the bone marrow donor in the region.This study was supported by the Russian Government Program of Competitive Growth of Kazan Federal University and «Rusfond». RAA was supported by state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of Russian Federation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8+ T Cells and Accumulation of HLA-Associated Escape Mutations.

The Gag280 mutation is associated with HLA-C*01:02 but not with HLA-B*52:01 in subtype A/E-infected individuals, whereas this mutation is associated with HLA-B*52:01 but not with HLA-C*01:02 in subtype B infections. Although it is known that the Gag280 mutant is selected by HLA-B*52:01-restricted GagRI8 (Gag275-282)-specific T cells in subtype B infections, it remains unknown why this Gag280 mutation is associated with HLA-C*01:02 rather than HLA-B*52:01 in subtype A/E infections. The subtype B and A/E viruses have different consensus sequence, with Thr and Val at Gag280, respectively. To clarify the effect of this difference in Gag280 consensus sequence, we investigated the role of HLA-C*01:02-restricted GagYI9 (Gag277-285)-specific T cells in selection of Gag280 mutations in subtype A/E-infected Vietnamese and subtype B-infected Japanese individuals. GagYI9-4V-specific T cells, which were frequently elicited in Vietnamese individuals infected with the consensus-type A/E virus, failed to recognize GagV280T mutant A/E virus-infected cells. GagYI9-4T mutant epitope-specific T cells, which were weakly elicited in individuals infected with the mutant A/E virus, had weak or no ability to recognize the mutant virus. These results account for the mechanism for selection and accumulation of GagV280T mutants in the case of subtype A/E infections. In contrast, HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in Japanese individuals infected with the subtype B virus, explaining why HLA-C*01:02-restricted Gag280 mutations are not accumulated in the case of a subtype B infection. The present study demonstrated that a difference in the Gag280 consensus sequence influenced the elicitation of the GagYI9-specific T cells involved in the accumulation of HLA-C*01:02-associated Gag280 mutations.IMPORTANCE HIV-1 mutations escaped from HIV-specific CD8+ T cells are mostly detected as HLA-associated mutations. A diversity of HLA-associated mutations is somewhat distinct to each race and region, since HLA allele distribution differs among them. A difference in the consensus sequence among HIV-1 subtypes may also influence the diversity of HLA-associated mutations. HLA-C*01:02-associated GagV280T and HLA-B*52:01-associated GagT280A/S mutations were previously identified in HIV-1 subtype A/E-infected and subtype B-infected individuals, respectively, though these subtype viruses have a different consensus sequence at Gag280. We demonstrated that the GagV280T mutant virus was selected by HLA-C*01:02-restricted GagYI9-4V-specific T cells in subtype A/E-infected Vietnamese but that HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in subtype B-infected Japanese. Together with our recent study which demonstrated the mechanism for the accumulation of HLA-B*52:01-associated mutations, we clarified the mechanism for the accumulation of different Gag280 mutations and the effect of the difference in the consensus sequence on the accumulation of escape mutations.

Corona Viruses and Human Leukocyte Antigen (HLA) alleles

Major histocompatibility complex (MHC) is consisted of cluster of genes known as human leukocyte antigen HLA, these genes are committed to process and present antigens to T lymphocyte. Corona viruses, belonging to a genus of the corona viridae family, are enveloped viruses containing single stranded RNA 27-32 kb. This study was conducted to highlight some observations that may help other researcher for rapid research advances; the new corona virus genome sequence was obtained from Virus pathogen database, the spike protein (surface glycoprotein) was aligned with SPIKE_CVHSA Spike glycoprotein OS=Human SARS coronavirus OX=694009 GN=S PE=1 SV=1 which was retrieved from Uniprot data base Distribution of HLA alleles was obtained from allele frequencies database, IEDB server was used for MHC 1 prediction. The distribution of HLA-A alleles among population revealed that, the most common wasHLA-A*11:01. The affinity prediction of HLA-A*03:01(AAAYFVGYLK) and HLA-A*11:01(AAYFVGYLK) alleles to the spike peptide were positive. The two positive predicted peptides for both 2 alleles showed mutation of K245Q, This mutation may affect the binding affinity of the protein peptides to HLA-A alleles.&#x0D; Keywords: HLA. MHC, alleles, Corona viruses, SARS, APS

Frequency analysis of HLA-B allele in leukemia patients from a North Indian population: A case-control study

BackgroundHLA-B gene is reported to have the highest number of allelic variants among the other HLA class I genes. It is suggested that the HLA-B gene has a particular ability to affect the activity of some immune responses mainly those related to lymphoproliferative neoplasia triggered by intracellular pathogens. Although, several studies have been conducted to study HLA polymorphism and distribution of HLA alleles in different populations and ethnic groups, the scarcity of comparable findings in India encouraged us to examine the possible HLA-B leukemia association in the North Indian population. ObjectiveTo determine the allelic frequencies of HLA-B and their association with leukemia in a North Indian population. Material and methodsA total of 583 patients (case) diagnosed with leukemia as well as 1188 healthy individuals (control) were studied for a period of 4 years (February 2015–March 2019). All these samples (cases and controls) were typed for HLA-B allele by polymerase chain reaction- sequence-specific oligonucleotide probe (PCR-SSOP) method based on Luminex platform. ResultsWe found an increased frequency of HLA-B*07:02 (5.75% versus 4.42%) in cases as compared to the control group. Similarly, frequency of HLA-B*15:01 (2.3% versus 1.38%), B*15:25 (0.43% versus 0.08%), B*18:01 (3.60% versus 2.81%) and B*44:03 (8.75% versus 6.01%) were found to be increased in cases as compared to the controls. These results suggest that HLA-B*15:25 (p = 0.048, OR = 4.49, 95% CI), 38:02 (p = 0.002, OR = 3.97, 95% CI), 44:03 (p = 0.003, OR = 1.48, 95% CI) have a positive association whereas HLA-B*08:01 (p ≤0.001, OR = 0.48, 95% CI) has a negative association with leukemia. ConclusionsOur results provide the first evidence of the HLA-B allele association with leukemia in the North Indian population. Further, it is suggested that HLA-B*15:25, B*38:02, and HLA-B*44:03 alleles may play a presumptive predisposing factor while the HLA-B*08: 01 allele could be a protective genetic factor against leukemia in the North Indian population.

Identification of HLA-A/B/DRB1 alleles in Iranian patients with Fanconi anemia.

Fanconi anemia includes a number of clinically and genetically diverse disorders all of them being associated with genomic instability. Some previous studies reported higher frequencies of certain HLA alleles in patients with Fanconi anemia. In the current study, we genotyped HLA-A/B/DRB1 alleles in 40 Iranian patients with Fanconi anemia. We also genotyped these alleles in the same number of Iranian sex-matched healthy individuals. The frequency of DRB1*11 was significantly higher in patients compared with controls (OR (95% CI) = 2.143 [1.05, 4.46], P value = 0.036). On the other hand, the frequencies of DRB1*13 and B*13 were lower in patients compared with controls (OR (95% CI) = 0.134 [0.02, 0.55], P value = 0.003 and OR (95% CI) = 0.13 [0.01, 0.89], P value = 0.035, respectively). Assessment of genetic divergence using Fstat test showed complete divergence in HLA-A, -B, -DRB1 alleles and haplotypes between patients and controls. The current study provides evidences for different distribution of HLA alleles between patients with Fanconi anemia and healthy subjects.