HLA-DRB1 Haplotypes Research Articles

HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10918 Koreans from bone marrow donor registry in Korea.

The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were mostdiverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease association studies.

Frequency of HLA-DRB1 and HLA-DQB1 Alleles and Haplotype Association in Syrian Population

ABSTRACTThe study of Human Leukocyte Antigen (HLA) system is very important in health and diseases. As the HLA loci are the most polymorphic in the human genome, it plays a very important role in the immune responses to self and nonself antigens. In the light of the growing importance of typing the HLA alleles in transplantation, autoimmune diseases, cancer, and many other diseases, we studied 225 unrelated healthy Syrian subjects for their HLA class II genotypes in an attempt to reveal the distribution of the HLA (DRB1-DQB1) alleles in the general Syrian population. Our results revealed that the most common alleles for the DRB1 locus were DRB1*11 (26.4%), DRB1*04 (14%), and DRB1*07 (12%). However, the most frequent alleles for the DQB1 locus were DQB1*03 (40.9%) and DQB1*05 (25.1%). The frequent of two-locus haplotypes carry the most frequent alleles at these loci. The most frequently detected class II ‘‘haplotypes’’ are DRB1*11-DQB1*03 (8.9%), DRB1*01-DQB1*05 (3.6%), and DRB1*04-DQB1*03 (2.7%). Compared with other populations, our result, deduced from the analysis of genetic distances and the construction of neighbor-joining (NJ) dendrogram, and principal component analysis (PCA) indicates that Syrians are related to Middle Eastern populations. Our data about the Syrian population will aid researchers in studying the relation of HLA class II with different diseases in a Syrian population and will add to the available international literature associated with these loci.

Immunity-mediated diseases and human immunogenetics (accomplishments and prospects)

Type 1 diabetes mellitus (T1DM) was used from the viewpoint of human immunogenetics as an example of the most widely studied immunity-mediated disease. This was done in order to develop, approve and implement a new clinical approach to determine immunity-mediated susceptibility or resistance to autoimmune diseases. The approach is based on analysis of entire HLA-DRB1 genotypes (not separate HLA-DRB1 haplotypes) of the study participants. Therefore, more effective and personalised classification of T1DM risk groups was achieved by exclusion from significant contingents.

Three deduced probable human-leukocyte-antigen haplotypes associated with HLA-DQB1*03:26 and -DRB1*14:141 from Taiwanese unrelated bone-marrow hematopoietic-stem-cell donors: Two case analyses

ObjectiveHLA-DQB1*03:26 and -DRB1*14:141 are two low-incidence alleles found at the HLA-DQB1 and HLA-DRB1 loci. The objective of this study was to report the ethnicity of DQB1*03:26 and DRB1*14:141, and their deduced probable HLA-associated haplotypes among Taiwanese unrelated bone-marrow hematopoietic-stem-cell donors. Materials and MethodsA sequence-based typing method was employed to confirm these two low-incidence alleles. Polymerase chain reaction was carried out to amplify exon 2 and exon 3 of the HLA-A and HLA-B loci, and exon 2 of the HLA-DRB1 and HLA-DQB1 loci using group-specific primer sets. The amplicons were then sequenced using a BigDye Terminator Cycle Sequencing Ready Reaction Kit in both directions according to the manufacturer's protocols. ResultsThe DNA sequence of DQB1*03:26 is most similar to DQB1*03:03:02:01 and DQB1*03:11 in exon 2. It differs from DQB1*03:03:02:01 at residue 136 where the A of DQB1*03:03:02:01 is replaced by the C of DQB1*03:26. This nucleotide exchange leads to an amino-acid alteration in the protein sequence of DQB1*03:03:02:01 at residue 14 where the methionine (M) of DQB1*03:03:02:01 is changed to the leucine (L) of DQB1*03:26. We deduced the probable HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 haplotypes associated with DQB1*03:26 in Taiwanese to be A*02:01-B*40:01-C*03:04-DRB1*08:03-DQB1*03:26 or A*02:01-B*40:01:C*03:04-DRB1*09:01-DQB1*03:26). DQB1*03:26 differs from DQB1*03:11 at residue 266 where the C of DQB1*03:11 is substituted by the A of DQB1*03:26. This nucleotide exchange leads to an amino-acid alteration to the protein sequence of DQB1*03:11 at residue 57 where the amino acid alanine (A) of DQB1*03:11 is replaced by the amino acid, aspartic acid (D), of DQB1*03:26. We also confirmed the DNA and protein sequences of RB1*14:141 and its ethnicity. The probable HLA-A, HLA-B, and HLA-DRB1 haplotypes associated with DRB1*14:141 in Taiwanese may be deduced to be A*02:03-B*15:25-DRB1*14:141. ConclusionInformation on the ethnicity of the DQB1*03:26 and DRB1*14:141 alleles, and the deduced probable HLA haplotypes associated with the low-incidence alleles that we report here is of value to HLA testing laboratories for reference purposes. In addition, they can be used by stem-cell-transplantation-donor-search coordinators in order to determine a strategy for finding compatible donors in unrelated bone-marrow-donor registries when patients carry these uncommon HLA alleles.

Prevalent HLA Class II Alleles in Mexico City Appear to Confer Resistance to the Development of Amebic Liver Abscess.

Amebiasis is an endemic disease and a public health problem throughout Mexico, although the incidence rates of amebic liver abscess (ALA) vary among the geographic regions of the country. Notably, incidence rates are high in the northwestern states (especially Sonora with a rate of 12.57/100,000 inhabitants) compared with the central region (Mexico City with a rate of 0.69/100,000 inhabitants). These data may be related to host genetic factors that are partially responsible for resistance or susceptibility. Therefore, we studied the association of the HLA-DRB1 and HLA-DQB1 alleles with resistance or susceptibility to ALA in two Mexican populations, one each from Mexico City and Sonora. Ninety ALA patients were clinically diagnosed by serology and sonography. Genomic DNA was extracted from peripheral blood mononuclear cells. To establish the genetic identity of both populations, 15 short tandem repeats (STRs) were analyzed with multiplexed PCR, and the allelic frequencies of HLA were studied by PCR-SSO using LUMINEX technology. The allele frequencies obtained were compared to an ethnically matched healthy control group (146 individuals). We observed that both affected populations differed genetically from the control group. We also found interesting trends in the population from Mexico City. HLA-DQB1*02 allele frequencies were higher in ALA patients compared to the control group (0.127 vs 0.047; p= 0.01; pc= NS; OR= 2.9, 95% CI= 1.09-8.3). The less frequent alleles in ALA patients were HLA-DRB1*08 (0.118 vs 0.238 in controls; p= 0.01; pc= NS; OR= 0.42, 95% CI= 0.19-0.87) and HLA-DQB1*04 (0.109 vs 0.214; p= 0.02; pc= NS; OR= 0.40, 95% CI= 0.20-0.94). The haplotype HLA-DRB1*08/-DQB1*04 also demonstrated a protective trend against the development of this disease (0.081 vs. 0.178; p=0.02; pc=NS; OR= 0.40, 95% CI= 0.16-0.93). These trends suggest that the prevalent alleles in the population of Mexico City may be associated with protection against the development of ALA.

Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.

Advances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response. To assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs. The Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989-2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986-1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990-2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006-2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry. Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74. Radiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response. Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51-2.05], P = 4.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16 [95% CI, 1.03-1.31], P = .01) (noncarriers: 319 deaths in 1398 patients over 17,196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13,208 person-years, mortality rate of 2.5% per year) and with better EULAR response to TNF inhibitor therapy (OR, 1.14 [95% CI, 1.01-1.30], P = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote carriers: 81% [698/866]; and homozygote carriers: 86% [277/322]). The risk hierarchy defined by HLA-DRB1 haplotypes was correlated between disease susceptibility, severity, and mortality, but inversely correlated with TNF inhibitor treatment response. Among patients with RA, the HLA-DRB1 locus, which is associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA.

HLA-A, HLA-B, and HLA-DRB1 Allele and Haplotype Frequencies in Renal Transplant Candidates in a Population in Southern Brazil.

Very few studies have examined the diversity of human leukocyte antigens (HLA) in the Brazilian renal transplant candidates. The frequencies of the HLA-A, HLA-B, and HLA-DRB1 alleles, haplotypes and phenotypes were studied in 522 patients with chronic renal failure, renal transplant candidates, registered at the Transplant Centers in north/northwestern Paraná State, southern Brazil. Patients were classified according to the ethnic group (319 whites [Caucasians], 134 mestizos [mixed race descendants of Europeans, Africans, and Amerindians; browns or "pardos"] and 69 blacks). The HLA typing was performed by the polymerase chain reaction sequence-specific oligonucleotide method (PCR-SSO), combined with Luminex technology. In the analysis of the total samples, 20 HLA-A, 32 HLA-B, and 13 HLA-DRB1 allele groups were identified. The most frequent allele groups for each HLA locus were HLA-A*02 (25.4%), HLA-B*44 (10.9%), and HLA-DRB1*13 (13.9%). The most frequent haplotypes were HLA-A*01-B*08-DRB1*03 (2.3%), A*02-B*44-DRB1*07 (1.2%), and A*03-B*07-DRB1*11 (1.0%). Significant differences (P < 0.05) were observed in the HLA-A*68, B*08, and B*58 allele frequencies among ethnic groups. This study provides the first data on the HLA-A, HLA-B, and HLA-DRB1 allele, phenotype and haplotype frequencies of renal transplant candidates in a population in southern Brazil.

Proceedings: human leukocyte antigen haplo-homozygous induced pluripotent stem cell haplobank modeled after the california population: evaluating matching in a multiethnic and admixed population.

The development of a California-based induced pluripotent stem cell (iPSC) bank based on human leukocyte antigen (HLA) haplotype matching represents a significant challenge and a valuable opportunity for the advancement of regenerative medicine. However, previously published models of iPSC banks have neither addressed the admixed nature of populations like that of California nor evaluated the benefit to the population as a whole. We developed a new model for evaluating an iPSC haplobank based on demographic and immunogenetic characteristics reflecting California. The model evaluates haplolines or cell lines from donors homozygous for a single HLA-A, HLA-B, HLA-DRB1 haplotype. We generated estimates of the percentage of the population matched under various combinations of haplolines derived from six ancestries (black/African American, American Indian, Asian/Pacific Islander, Hispanic, and white/not Hispanic) and data available from the U.S. Census Bureau, the California Institute for Regenerative Medicine, and the National Marrow Donor Program. The model included both cis (haplotype-level) and trans (genotype-level) matching between a modeled iPSC haplobank and the recipient population following resampling simulations. We showed that serving a majority (>50%) of a simulated California population through cis matching would require the creation, redundant storage, and maintenance of almost 207 different haplolines representing the top 60 most frequent haplotypes from each ancestry group. Allowances for trans matching reduced the haplobank to fewer than 141 haplolines found among the top 40 most frequent haplotypes. Finally, we showed that a model optimized, custom haplobank was able to serve a majority of the California population with fewer than 80 haplolines.

High-resolution HLA-A, HLA-B, and HLA-DRB1 haplotype frequencies from the French Bone Marrow Donor Registry

We have estimated human leukocyte antigen (HLA) haplotype frequencies using the maximum likelihood mode, which accommodates typing ambiguities. The results of the frequency distribution of the 7015 haplotypes obtained are presented here. These include a total of 114 HLA-A, 185 HLA-B, and 76 HLA-DRB1 unique alleles at each locus. Across all populations, although the most common individual HLA alleles were HLA-A∗02:01 (29.0%), HLA-B∗07:02 (11.4%), and HLA-DRB1∗07:01 (15.9%), the most frequent haplotype was found to be HLA-A∗01:01∼B∗08:01∼DRB1∗03:01.

The HLA-DQA1–HLA-DRB1 haplotype is linked to risk of thiopurine-induced pancreatitis in IBD

The HLA-DQA1–HLA-DRB1 haplotype is linked to risk of thiopurine-induced pancreatitis in IBD

CYP21A2 polymorphisms in patients with autoimmune Addison's disease, and linkage disequilibrium to HLA risk alleles.

Steroid 21-hydroxylase, encoded by CYP21A2, is the major autoantigen in autoimmune Addison's disease (AAD). CYP21A2 is located in the region of the HLA complex on chromosome 6p21.3, which harbours several risk alleles for AAD. The objective was to investigate whether CYP21A2 gene variants confer risk of AAD independently of other risk alleles in the HLA loci. DNA samples from 381 Norwegian patients with AAD and 340 healthy controls (HC) previously genotyped for the HLA-A, -B, -DRB1, and -DQB1 and MICA loci were used for genotyping of CYP21A2. Genotyping of CYP21A2 was carried out by direct sequencing. Linkage of CYP21A2 to the HLA loci was assessed using UNPHASED version 3.0.10 and PHASE version 2.1. Heterozygotes of the single-nucleotide polymorphisms (SNPs) rs397515394, rs6467, rs6474, rs76565726 and rs6473 were detected significantly more frequently in AAD patients compared with HC (P<0.005), but all SNPs were in a linkage disequilibrium (LD) with high-risk HLA-DRB1 haplotypes. rs6472C protected against AAD (odds ratio=0.15, 95% CI (0.08-0.30), P=3.8×10(-10)). This SNP was not in an LD with HLA loci (P=0.02), but did not increase protection when considering the effect of HLA-DRB1 alleles. Mutations causing congenital adrenal hyperplasia were found in heterozygosity in <1.5% of the cases in both groups. Genetic variants of CYP21A2 associated to AAD are in LD with the main AAD risk locus HLA-DRB1, and CYP21A2 does not constitute an independent susceptibility locus.

OP0190 Personalized Genetic Medicine: Amino Acid Positions 11, 71 and 74 in HLA-DRB1 PREDICT Disease Severity, Treatment Response and Mortality in Rheumatoid Arthritis; Multi-Centre Prospective Cohort Studies

BackgroundThe shared epitope (SE) is a group of alleles of the HLA DRB1 gene and was thought to have the strongest effect on rheumatoid arthritis (RA) susceptibility. However, recently, HLA-DRB1...

HLA-A, HLA-B and HLA-DRB1 allele and haplotype diversity among volunteer bone marrow donors from Croatia.

The determination of human leucocyte antigen (HLA)-A, HLA-B and HLA-DRB1 alleles in the routine procedure of a volunteer hematopoietic stem cell (HSC) donor's registration in the Croatian Bone Marrow Donor Registry (CBMDR) is performed to enhance the odds of finding a suitable HLA compatible donor for patients in need of a HSC transplantation worldwide. However, besides its original purpose, it also provides valuable information about the HLA polymorphism among Croats. The aim of the present study was to analyse the HLA allele and haplotype frequencies in a sample of 4000 donors from CBMDR. The distribution of HLA-A, HLA-B and HLA-DRB1 alleles did not demonstrate significant differences from the data reported for other European populations. The higher frequency of B*40:02 allele in comparison with B*40:01 and DRB1*11:04 in comparison with DRB1*11:01 is interesting because it represents a difference in comparison with the Western and Northern European populations which are a main source of donors for Croatian patients. The haplotype frequencies show a greater variation and difference in comparison with data from other registries and populations; however, due to a lack of high-resolution haplotype data, comparison was possible only with a very limited number of other populations.

The clinical value of human leukocyte antigen HLA-DRB1 subtypes associated to Graves’ disease in Romanian population

The aim of this study was to identify the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population and to seek whether specific HLA-DRB1 haplotypes are associated with differences in the clinical presentation of GD at diagnosis. Molecular typing of HLA-DRB1 alleles was performed in 77 Romanian Caucasian GD patients and 445 racially matched controls. In GD patients, age, presence of eye disease, goiter grade, autoantibody status and titer, TSH, FT4, FT3, TT3 levels were recorded at diagnosis. The allelic frequencies of HLA-DRB1*03 (41.55% vs. 17.75%, p < 0.0001, χ2 = 20.81) and DRB1*11 (42.85% vs. 30.56%, p = 0.045, χ2= 3.98)were higher, whereas those of HLA-DRB1*01(3.89% vs. 16.40%, p = 0.007, χ2 = 7.281) and DRB1*15 (10.38% vs. 21.34%, p = 0.038, χ2 = 4.309)were lower in GD patients than in controls. FT4/TT3 ratio (p = 0.015) and anti-thyroglobulin antibodies (p = 0.024) were higher in *03/11 patients compared to *X/X, *11/Z, *03/Y patients (where X is any other allele than *03 and *11, Y is any other allele than *11, Z is any other allele than *03). In conclusion, HLA-DRB1*03 and DRB1*11 may be the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population, whereas HLA-DRB1*01 and DRB1*15 seem to be protective. At diagnosis, HLA-DRB1*03/11 GD patients had higher FT4/TT3 ratio and anti-thyroglobulin antibody levels.

Meta-Analysis on the Relationship between HLA-DRBl Gene Polymorphism and Cervical Cancer in Chinese Population

AimTo determine the association between HLA-DRB1 haplotypes and risk of cervical cancer in unselected and samples from Chinese ethnicities.MethodsA comprehensive search for articles from their inception to April 1st, 2013 was conducted from PubMed, Medline, Elsevier Science, Springer Link, Cochrane Library database, China biology medical literature database (CBM),China National Knowledge Infrastructure (CNKI),VIP,and Chinese literature database(Wang fang). A total of 1596 patients with cervical cancer and 2048 controls from the 12 studies on the relationship between gene polymorphism of HLA-DRB l and cervical cancer were performed and data were analyzed and processed using Review Manager 5.0 and Stata 11.0.ResultsAmong the 13 family alleles, two (DRB1*03 and DRB1*08) were found to be negatively associated with cervical cancer in all studies or in Uighur subgroups, and two (DRB1*10 and DRB1*15) were positively associated with in all studies or in Uighur subgroups. Among the 25 specific alleles, six (DRB1*0301, *0403,*0404, *0803, *1312 and *1502) were associated with an increased risk cervical cancer in all studies. No significant association was established for other HLA-DRB1 family alleles and specific alleles. Ethnicity partially explained the race influence of DRB1*12, DRB1*14, DRB1*0301, DRB1*0403, DRB1*0404, DRB1*0803, DRB1*1312 and DRB1*1502 phenotypes.ConclusionOur results support the hypothesis that the HLA-DRB1 family alleles and specific alleles might influence the susceptibility or resistance to cervical cancer, suggesting that immune regulation may play a key role in this disease, although further investigations are still needed.

Research of HLA II Class DRB1, DQA1, DQB1 Genetic Markers in Patients with HIV Infection and AIDS

Aims: To find out the most frequent associations of the HLA II class loci DRB1*, DQA1*, DQB1* with the HIV/AIDS infection. Place and Duration of Study: The study took place in The Laboratory of Clinical Immunology and Immunogenetics (LCII) of Riga Stradiņs University (RSU), Riga, Latvia, Riga Eastern Clinical University Hospital, “Infectology Centre of Latvia”, between May 1991 and December 2004. Original Research Article British Journal of Medicine & Medical Research, 4(17): 4482-4500, 2014 4483 Methodology: We analysed the medical documentation of 2500 patients and included 1180 (888 men, 292 women, 185 of them in AIDS phase) HIV infected patients. Genomic DNA was extracted from the blood with phenol-chloroform extraction method. Lowresolution HLA typing for HLADRB1*; DQB1*; DQA1* was performed by polymerise chain reaction (PCR) with amplification with sequence-specific primers (SSP). PCR products were separated on 3% agarose, the amplified bands were visualized, and the HLA-DRB1; DQA1; DQB1 type was deduced. Results: Genetic markers of immunologic alleles upon development of HIV infection – HLA-DRB1*03(17:01); 05(11:01); 07:01; HLA-DQA1*01:01; 02:01; 03:01; 06:01; HLADQB1* 03:02; 05:01; 03:03; 03:04, as well as resistance markers connected with slow development of HIV infection – HLA-DRB1*01:01; 04:01; 06(13:01); HLA-DQA1*01:03; 04:01; 05:01; HLA-DQB1*03:01; 03:03; 04:01-2; 06:01; 06:02-8 are located in different groups of patients. High risk markers in case of HIV infection development belonging to the following groups of alleles: HLA-DRB1*03(17:01), DRB1*05(11:01), DQA1*01:01; 03:01 un DQB1*05:01; 03:02, as well as three-loci haplotypes HLA-DRB1*03(17:01)/ DQB1*05:01/ DQA1*01:01; HLA-DRB1*05(11:01)/DQB1*03:01/ DQA1 *05:01; DRB1*01:01/DQB1*03:02/ DQA1*03:01 and DRB1*01:01/DQB1*05:01/DQA1*01:01 are determined. Resistance to HIV infection development forms in the following groups of alleles: HLA-DRB1*01:01; 06(13:01), HLA-DQB1* 03:01; 06:02-8; HLA-DQA1*01:02; 01:03, as well as in haplotypes HLADRB1*01:01/DQB1*06:02-8/DQA1*01:02;HLADRB1*06(13:01)/DQB1*06:02-8/DQA1*01:02; HLADRB1*01:01/DQB1*03:01/DQA1*01:02; and HLA-DRB1*06(13:01)/DQB1*06:02-8/ DQA1*01:02 in different groups of HIV/AIDS patients. Conclusion: The prevalence of genes DRB1; DQA1; DQB1 and DRB1-DQA-DQB1 combinations in the five groups of HIV infected patients have been established. Comparative analysis was performed also in the group of healthy donors (control group). The role of the main histocompatibility complex has been established, it enables marker functions and that can be used in the additional prognostic diagnostics in case of HIV infection. The obtained results testify that upon the identification of HIV genes it is possible to understand the molecular mechanisms in case of progression of AIDS syndrome complex; this possibly can be beneficial for the determination of the clinical results of infected patients.

HLA phenotypes of candidates for HSCT: comparing transplanted versus non‐transplanted candidates, resulting in the predictive estimation of the probability to find a 10/10 HLA matched donor

In order to study the impact of human leucocyte antigen (HLA) polymorphism distribution in identifying a matched haematopoietic stem cells unrelated donor (UD), we performed a multi-centric retrospective analysis with the aim of comparing the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 phenotypes of 2126 patients (772 patients for whom a donor search failed to identify a matched UD, and 1354 patients who received a 10/10 allele level matched UD). Our results showed that rare HLA-C is often responsible for difficulty in identifying a donor. This locus may add a degree of complexity to a supposed 'frequent' HLA-A HLA-B and HLA-DRB1 phenotype, turning this phenotype into a less frequent one. For example, 32.5% of the phenotypes in the non-transplanted patients could not be explained by any of the pairs of known HLA-A, HLA-B, HLA-C and HLA-DRB1 haplotypes while this percentage dropped to less than 2% if combinations of only HLA-A, HLA-B and HLA-DRB1 haplotypes were considered. Such situations can be anticipated by computing an index, based on HLA haplotype frequency, the average registry sample size (ARS). ARS is defined as the inverse of the phenotype frequency computed using all corresponding pairs of haplotype frequencies. ARS confirmed that the most significant difference between transplanted and non-transplanted patients was correlated with the introduction of the locus HLA-C in the analysis (median: 8.3e + 4 vs 3.1e + 6, P < 0.0001). The higher the ARS the lower the likelihood of finding a 10/10 match UD reflecting the rareness of the patient's HLA. The area under receiver operator characteristics (AUROC) values of the ARS computation for HLA-A, HLA-B and HLA-DRB1 was 0.82 (0.80; 0.84) at a low-resolution level (two digits). Overall, our study promotes the use of haplotype frequency-based computations to develop computer-assisted donor search.

Diversity of Extended HLA-DRB1 Haplotypes in the Finnish Population

The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes.

HLA-A, HLA-B and HLA-DRB1 haplotype frequencies in Piauí’s volunteer bone marrow donors enrolled at the Brazilian registry

This study aimed to report the antigen and haplotype frequencies (HFs) of volunteer bone marrow donors (VBMDs) from the state of Piauí who were enrolled in the National Volunteer Bone Marrow Donor Registry (REDOME). The research subjects were 21,943 volunteer bone marrow donors, predominantly young adult women (53.3%). The most frequent allelic group was HLA-A2, followed by -DRB1*13, -DRB1*04, -DRB1*07, -B*15, -B∗35, -B*44, -A*24 and -A*03.Of the 2,704 haplotypes observed, the three most frequent haplotypes were A*29 B*44 DRB1*07 (1.45%), A*01 B*08 DRB1*03 (1.4%) and A*03 B*07 DRB1*15 (0.92%). These three haplotypes were in linkage disequilibrium.PCA showed that 98% of the VBMDs have HLA allele frequencies that are very similar to those from Teresina, the capital city of Piauí. According to the PCA results, these municipalities are distributed with a close proximity to Teresina, which in turn has a close genetic proximity to the Hispanic ethnicity, intermediate proximity to Caucasians and Africans and a distant kinship to Amerindians. The hierarchical proximity of the population of Piauí to the Portuguese and Hispanic populations to shows the strong influence of the latter on the former.

HLA-DRB1 Shared Epitope-Dependent DR-DQ Haplotypes Are Associated with Both Anti-CCP–Positive and –Negative Rheumatoid Arthritis in Chinese Han

The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10−6). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10−13). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10−13) and -negative RA (P = 3.89×10−5). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.