HLA-B Polymorphisms Research Articles

The interplay between HLA-B and NLRP3 polymorphisms may be associated with the genetic susceptibility of gout.

HLA and NLRP3 play an important role in the development of various autoimmune and autoinflammatory diseases. Gout is an autoinflammatory disease associated with multiple genetic and environmental factors. The objective of the present study was to evaluate the interaction and association between genetic polymorphisms of HLA-B and the NLRP3 gene in Mexican patients with gout. Eighty-one patients with gout were included and compared with 95 healthy subjects. The polymorphisms rs4349859, rs116488202, rs2734583 and rs3099844 (within the HLA-B region) and rs3806268 and rs10754558 of the NLRP3 gene were genotyped using TaqMan probes in a Rotor-Gene device. The interactions were determined using the multifactorial dimensionality reduction (MDR) method, while the associations were determined through logistic regression models. The MDR analysis revealed significant interactions between the rs116488202 and rs10754558 polymorphisms with an entropy value of 4.31% (p < 0.0001). Significant risk associations were observed with rs4349859 and rs116488202 polymorphisms (p < 0.01); however, no significant associations were observed with the polymorphisms of the NLRP3 gene. The results suggest that HLA-B polymorphisms and their interaction with NLRP3 may contribute to the genetic susceptibility of gout.

Association Between HLA-B Polymorphisms and Autism Spectrum Disorder in Chinese Population

Objectives: The aim of this study was to investigate the association between 2 single-nucleotide polymorphisms (SNP) of HLA-B and autism spectrum disorder (ASD). Methods: We enrolled 84 ASD and 182 healthy children in case-control study, and 67 family trios in family-based study. Two tag SNPs (rs1058026, rs2770) in gene HLA-B were selected to determine the association with ASD. Chi-square test was used in case-control study, haplotype relative risk test (HRR) and transmission disequilibrium test (TDT) analysis were performed in family-based study. Results: SNP rs1058026 was found significantly associated with ASD in family-based study (P = 0.016 for HRR; P = 0.020 for TDT), but not in case-control study. Conversely, SNP rs2770 did not show association with ASD in both studies. Conclusions: The association observed from this study indicates that gene HLA-B might play a role in ASD in Chinese population.

Causative drugs and HLA-B polymorphism in drug-induced Stevens-Johnson syndrome - toxic epidermal necrolysis: A study in five hospitals in Jakarta

Stevens-Johnson syndrome and toxic epidermal necrolysis is a very rare but lifethreatening form of cutaneous drug eruption. In recent years, several countries in Asia had succeded in preventing carbamazepine induced SJS/TEN by screening for HLA-B*15:02 before prescribing carbamazepine. This study aimed to acquire data regarding causative drugs and HLA-B allele polymorphism in SJS/TEN patient in Jakarta. We acquired data from 5 referral hospitals from March 2015 to March 2017. Subject fulfilling the inclusion and exclusion criteria was interviewed and blood sample was taken for DNA extraction. The DNA was examined with PCR SSOP and Luminex technology for high resolution HLA-B typing. We studied 22 subjects. The median age was 45,4 years old (14-74). The most common causative drug in this study is carbamazepine. HLA-B*15:02 and HLAB* 18:01 were the most common allele in all subjects. HLA-B*15:02 was found in five (72%) out of seven subjects whose condition was caused by carbamazepine. The most common causative drug of SJS/TEN in five hospitals in Jakarta is carbamazepine, with five (72%) out seven subjects had HLA-B*15:02 allele.

An historical approach to the genetic distribution of KIR and HLA ligands in Eastern Sicilians compared to modern descendants of their invaders

A geographical stratification of Killer Immunoglobulin-like Receptors (KIR) has been reported worldwide. We first analyzed the distribution of 15 KIR genes in a sample of 50 East-Sicilians (ES). We used a Principal Component Analysis (PCA) to compare the KIR genetic content among ES and 10 modern populations who are descendants of the ancient invaders of Sicily: Spanish, French, Norwegians, Swedes, Finns, Tunisians, Moroccans, Arabs, Greeks, Turks. We also included a sample of Sardinians, and Senegalese (as outlier group). Then, we also compared the HLA-A, HLA-B and HLA-C allelic frequencies among ES and the same populations investigated for KIR. As to HLA-A and HLA-B polymorphisms, ES are close to Greek population who invaded the island for long time until 827 CE; while HLA-C and KIR distribution in ES are close to Spanish population that invaded Sicily (and Sardinia) starting from 1283. As to KIR, ES are close to Spanish and Sardinians. The immunogenetic fingerprint of ES may be the finely balanced result of the invasions that overwhelmed Sicily over the centuries.

HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms

Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions—the B and F pockets—of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (GST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and GST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-015-0875-9) contains supplementary material, which is available to authorized users.

HLA-B polymorphisms and intracellular assembly modes.

Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV-infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells.

HLA-B allele and haplotype diversity among Thai patients identified by PCR-SSOP: evidence for high risk of drug-induced hypersensitivity.

Background: There are 3 classes of HLA molecules; HLA class I, II and III, of which different classes have different functions. HLA-B gene which belongs to HLA class I play an important role predicting drug hypersensitivity.Materials and Methods: Nine hundred and eighty-six Thai subjects who registered at a pharmacogenomics laboratory were determined for HLA-B genotype using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP).Results: In this study, HLA-B alleles did not deviate from Hardy-Weinberg equilibrium (P > 0.05). The most common HLA-B alleles observed in this population were HLA-B*46:01 (11.51%), HLA-B*58:01 (8.62%), HLA-B*40:01 (8.22%), HLA-B*15:02 (8.16%) and HLA-B*13:01 (6.95%). This finding revealed that HLA-B allele frequency in the Thai population was consistent with the Chinese population (p > 0.05), however, differed from the Malaysian population (p < 0.05). The top five HLA-B genotypes were HLA-B*40:01/46:01 (2.13%), HLA-B*46:01/46:01 (2.03%), HLA-B*40:01/58:01 (2.03%), HLA-B*46:01/58:01 (1.93%) and HLA-B*15:02/46:01 (1.83%). This study found that 15.92% of Thai subjects carry HLA-B*15:02, which has been associated with carbamazepine-induced severe cutaneous adverse drug reactions (SCARs). Moreover, 16.33% of Thai subjects carry the HLA-B*58:01 allele, which has been associated with allopurinol-induced SCARs.Conclusion: This study demonstrates a high diversity of HLA-B polymorphisms in this Thai population. The high frequency of HLA-B pharmacogenomic markers in the population emphasizes the importance of such screening to predict/avoid drug hypersensitivity.

HLA-B alleles associate consistently with HIV heterosexual transmission, viral load, and progression to AIDS, but not susceptibility to infection.

HLA class I polymorphism is known to affect the rate of progression to AIDS after infection with HIV-1. Here we test the consistency of HLA-B allelic effects on progression to AIDS, heterosexual HIV transmission, and 'set point' viral levels. We used adjusted Cox proportional hazard models in previously published relative hazard values for the effect of HLA-B alleles on progression to AIDS (n = 1089). The transmission study included 303 HIV-1-infected men with hemophilia and their 323 female sex partners (Multicenter Hemophilia Cohort Study cohort). Among 259 HIV-1 seroconverters (Multicenter AIDS Cohort Study cohort), HIV RNA levels at 'set point' were determined in stored plasma samples by a reverse-transcription polymerase chain reaction assay. HLA-B genotyping was performed by sequence-specific oligonucleotide hybridization and DNA sequencing. Several HLA-B alleles showed consistent associations for AIDS risk, infectivity, and 'set point' HIV RNA. HLA-B*35 was associated with more rapid progression to AIDS (relative hazard 1.39; P = 0.008), greater infectivity (odds ratio 3.14; P = 0.002), and higher HIV RNA (P = 0.01), whereas the presence of either B*27 or B*57 associated with slower progression to AIDS (B*27: relative hazard 0.49, P < 0.001; B*57: relative hazard 0.40, P < 0.0001), less infectivity (odds ratio 0.22 and 0.31, respectively, though not significant), and lower viral levels (P < 0.0001). Importantly, HLA-B polymorphism in female partners was not associated with susceptibility to HIV-1 infection. HLA-B polymorphisms that affect the risk of AIDS may also alter HIV-1 infectivity, probably through the common mechanism of viral control, but they do not appear to protect against infection in our cohort.

Polymorphisms of HLA-A and HLA-B genes in genetic susceptibility to esophageal carcinoma in Chaoshan Han Chinese

Esophageal carcinoma (EC) occurs at high rate in Chaoshan region of southern China. Human leukocyte antigen (HLA) polymorphism has been implicated in risk for various cancers. To investigate the impact of HLA-A and HLA-B polymorphisms on susceptibility to EC, a case-control study was conducted among 206 patients with esophageal squamous cell carcinoma and 524 controls from Chaoshan Han population. HLA-A and HLA-B polymorphisms were genotyped by polymerase chain reaction-sequence-specific primers. Genotypic association tests for dominant, recessive, and additive models, and haplotypic association were calculated using unconditional logistic regression. A*11 was identified in a recessive model as an only allele strongly associated with EC risk (odds ratios [OR]=2.10, 95% confidence interval [CI]=1.33-3.31) even after correction for multiple test. The haplotypes A*02-B*46 (OR=1.53, 95% CI=1.04-2.24) and A*11-B*51 (OR=2.29, 95% CI=1.20-4.40) showed association with increased risk for EC, whereas A*11-B*58 (OR=0.00, 95% CI=0.00-0.82) was associated with decreased risk, though the significance of these haplotypes was lost after correction. This is a first association study at genetic level identifying HLA-A and HLA-B-related variations in genetic susceptibility to EC among Chaoshan population. The variation pattern is likely to be EC-specific because it is different from that observed for nasopharyngeal carcinoma in the same study population and might, at least in part, explain the high rate of EC in this ethnic group.

MICA-HLA-B haplotype diversity and linkage disequilibrium in a population of Jewish descent from Majorca (the Balearic Islands)

The major histocompatibility complex class I chain-related A (MICA) gene is located 46 kb centromeric of human leukocyte antigen (HLA)-B and is highly polymorphic, similar to HLA genes. This allelic variation may influence the affinity of MICA molecules to their receptor on natural killer, γδ T and CD8 + T cells, NKG2D, and the immune response to organ transplantation and disease susceptibility. In the present study, we typed MICA and HLA-B polymorphisms in 95 individuals from a population of Jewish descent (Chuetas) and 195 individuals of Caucasian origin from Majorca (the Balearic Islands). MICA*008, -*004, and -*002 were the most common alleles and accounted for 53 and 60% in Chuetas and Majorcans, respectively. Other common alleles (frequency >5%) were MICA*016, -*009, -*012, -*007, and -*017 in Chuetas and -*009, -*001, and -*018 in Majorcans. We also studied two-locus haplotype diversity and linkage disequilibrium (LD). Both populations presented haplotypes with significant LD that were shared by other Caucasians populations, but we reported particular haplotypes in the Chueta group: MICA*002–HLA-B*38, MICA*016–HLA-B*35, MICA*012–HLA-B*55, and MICA*017–HLA-B*57. These haplotypes were not reported in other studies at high frequencies. In conclusion, the Chueta population presents a particular genetic pool but has affinities with the host population.

Diversity of MICA and Linkage Disequilibrium with HLA-B in Two North American Populations

The MICA gene has a high degree of polymorphism. Allelic variation of MICA may influence binding of these ligands to the NK cell receptor NKG2D and may affect organ transplantation and/or disease pathogenesis. Knowledge of the population distribution of MICA alleles and their linkage disequilibrium (LD) with class I human leukocyte antigen (HLA) will enhance our understanding of the potential functional significance of the MICA polymorphism. In the present study, we characterized the MICA and HLA-B polymorphisms in two North American populations: European and African. The individual racial groups showed rather limited variation at the MICA locus, where the same set of three most common alleles, MICA*00201, *004, and *00801, account for 64 and 71% of the allele frequency in European-Americans and African-Americans, respectively. Other common alleles (allele frequency >5% in a population) include MICA*00901 and *010. MICA alleles showed strong linkage disequilibrium with HLA-B. Typically, a common MICA allele has strong LD with several HLA-B alleles, whereas most HLA-B alleles and their related serological groups are associated with a single MICA allele. The lack of evidence for an active diversification of the MICA gene after racial separation indicates an evolutionary history distinct from that of the classical HLA genes.

HLA-B Polymorphism in Japanese HIV-1–Infected Long-Term Surviving Hemophiliacs

Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIV-infected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR = 6.40, p = 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR = 0.22, p = 0.016). HLAB* 5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.

Analysis of HLA-B polymorphism in insulin dependent diabetes mellitus in Japanese.

Analysis of HLA-B polymorphism in insulin dependent diabetes mellitus in Japanese.

HLA-B polymorphism affects interactions with multiple endoplasmic reticulum proteins.

To explore the nature of amino acid substitutions that influence association with TAP, we compared a site-directed mutant of HLA-B*0702 (Y116D) to unmutated HLA-B7 in regard to TAP interaction. We found that the mutant had stronger association with TAP, and, in addition, with tapasin and calreticulin. These data confirm the importance of position 116 for TAP association, and indicate that (1) an aspartic acid at the 116 position can facilitate the interaction, and (2) association with tapasin and calreticulin is affected along with TAP. Furthermore, we tested three natural subtypes of HLA-B15, and found that a B15 subtype with a tyrosine at position 116 (B*1510) was strongly associated not only with TAP, but also with tapasin and calreticulin. In contrast, two B15 subtypes with a serine at position 116 (B*1518 and B*1501) exhibited very little or no association with any of these proteins. Thus, very closely related HLA-B subtypes can differ in regard to interaction with the entire assembly complex. Interestingly, when their surface expression was tested by flow cytometry, the HLA-B15 subtypes with little to no detectable intracellular assembly complex association had a slightly, yet consistently, higher level of the open heavy chain form than did the B15 subtype with intracellular assembly complex association. These data suggest that the relatively low strength or short length of interaction between endoplasmic reticulum proteins and natural HLA class I molecules can decrease their surface stability.

Sequence-Based Typing Provides a New Look at HLA-C Diversity

Although extensive HLA-A and HLA-B polymorphism is evident, the true diversity of HLA-C has remained hidden due to poor resolution of HLA-C Ags. To better understand the polymorphic nature of HLA-C molecules, 1823 samples from the National Marrow Donor Program research repository in North America have been typed by DNA sequencing and interpreted in terms of HLA-C diversification. Results show that HLA-Cw*0701 was the most common allele with a frequency of 16%, whereas 28% of the alleles typed as Cw12-18 (serologic blanks). The frequency of homozygotes was 9.8% as compared with previous studies of 18% for sequence-specific primers and 50% for serology. Most startling was the frequency at which new alleles were detected; 19 new HLA-C alleles were detected, representing a rate of approximately 1 in 100 samples typed. These new HLA-C alleles result from 29 nucleotide substitutions of which 4 are silent, such that coding substitutions concentrated about the Ag-binding groove predominate. Polymorphism at the HLA-C locus therefore resembles that at the HLA-A and HLA-B loci more than previously believed, indicating that antigenic stress is driving HLA-C evolution. However, sequence conservation in the alpha-helix of the first domain and a clustering of unique amino acids around the B pocket indicate that HLA-C alleles respond to antigenic pressures differently than HLA-A and HLA-B. Finally, because the samples characterized were predominantly from Caucasians, we hypothesize that HLA-C polymorphism will equal or exceed that of the HLA-A and -B loci as DNA sequence-based typing is extended to include more non-Caucasian individuals.

New highly polymorphic microsatellite marker in linkage disequilibrium with HLA-B

The difficulty of molecular typing of the HLA class I genes and the relevance of the genes of this region to disease susceptibility and transplantation have provided an impetus to develop useful typing markers. We have characterized by polymerase chain reaction analysis a new highly informative CA repeat localized approximately 25-kb centromeric to the gene HLA-B and 10-kb telomeric to the gene MICA. Twelve alleles defined by length were found in a sample of French Basques, with the PIC being 0.82. A detailed haplotype analysis was performed to investigate the association between this microsatellite and two others markers of the region (HLA-B gene and TNF region microsatellite). The 10 haplotypes with the highest estimated frequencies show evidence of a gametic association or linkage disequilibrium. A very strong association between the expressed HLA-B polymorphism and microsatellite alleles was also revealed in this sample and confirmed in the workshop cells lines of the Fourth Asia-Oceania Histocompatibility Workshop. This marker can be used in the fine mapping of this region and the association with some alleles of HLA-B may allow the replacement of HLA-B typing at least in a preliminary study. Moreover, these studies support the hypothesis of a high mutability for large alleles in microsatellite loci.