Dataset Information

HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

ABSTRACT: Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10??). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P(combined) = 3.59 × 10?¹?, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

SUBMITTER: Miki D

PROVIDER: S-EPMC3871580 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

Miki Daiki D Ochi Hidenori H Takahashi Atsushi A Hayes C Nelson CN Urabe Yuji Y Abe Hiromi H Kawaoka Tomokazu T Tsuge Masataka M Hiraga Nobuhiko N Imamura Michio M Kawakami Yoshiiku Y Aikata Hiroshi H Takahashi Shoichi S Akuta Norio N Suzuki Fumitaka F Ikeda Kenji K Kumada Hiromitsu H Karino Yoshiyasu Y Toyota Joji J Tsunoda Tatsuhiko T Kubo Michiaki M Kamatani Naoyuki N Nakamura Yusuke Y Chayama Kazuaki K

PloS one 20131220 12

Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese c ...[more]

PMID: 24376798

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Project description:Single-nucleotide polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene are associated with chronic inflammatory and immunological diseases. Host genetic factors have a key role in the development of chronic hepatitis B (CHB). The aim of the present study was to investigate the association between the HLA-DQB1 polymorphisms and the susceptibility to CHB. PubMed, Embase, CNKI and Wanfang databases were searched for the studies that reported the association of the HLA-DQB1 polymorphisms with CHB between January 1, 1966 and July 30, 2015. HLA-DQB1 polymorphism-specific odds ratio (OR) and 95% confidence intervals (95% CI) were pooled and calculated in the fixed effects model using the Mantel-Haenszel method. Q-test and I2 test were performed to examine the heterogeneity. Begg's funnel test and Egger's test were conducted to assess publication bias. All the statistical tests were two-tailed. Subsequent to searching the databases and screening according to the inclusion criteria, 7 case-control studies were available in the present meta-analysis, including 815 CHB patients and 731 control subjects for the HLA-DQB1 polymorphisms. In conclusion, the statistically significant pooled OR of the HLA-DQB1 polymorphisms were obtained for the HLA-DQB1 loci (*0201, case vs.ControlI2=36.5%; P-value of heterogeneity=0.15; OR, 1.29; 95% CI, 1.02-1.64; P=0.0301; *0301, case vs.ControlI2=0%; P-value of heterogeneity=0.899; OR, 1.37; 95% CI, 1.12-1.69; P=0.002; *0502, case vs.ControlI2=24.9%; P-value of heterogeneity=0.239; OR, 1.50; 95% CI, 1.02-2.20; P=0.04), which were associated with an increased risk of CHB. Similar significant results were observed and acquired in the following HLA-DQB1 loci (*0303, case vs.ControlI2=0%; P-value of heterogeneity=0.986; OR, 0.77; 95% CI, 0.62-0.95; P=0.017; *0604, case vs.ControlI2=0%; P-value of heterogeneity=0.594; OR, 0.38; 95% CI, 0.20-0.74; P=0.003), which were associated with a decreased risk of CHB. No significant association was observed for the other HLA-DQB1 family loci. The present meta-analysis demonstrated that the HLA-DQB1 loci (*0201, *0301 and *0502) polymorphisms were significantly associated with an increased risk of CHB. However, HLA-DQB1 loci polymorphisms (*0303 and *0604) were associated with a decreased risk of CHB. These results support the hypothesis that polymorphisms of the HLA-DQB1 allele families may affect the susceptibility or resistance to CHB.

Project description:BackgroundHLA-E interaction with inhibitory receptor, NKG2A attenuates NK-mediated cytotoxicity. NKG2A overexpression by SARS-CoV-2 exhausts NK cells function, whereas virus-induced down-regulation of MHC-Ia reduces its derived-leader sequence peptide levels required for proper binding of HLA-E to NKG2A. This leads HLA-E to become more complex with viral antigens and delivers them to CD8+ T cells, which facilitates cytolysis of infected cells. Now, the fact that alleles of HLA-E have different levels of expression and affinity for MHC Ia-derived peptide raises the question of whether HLA-E polymorphisms affect susceptibility to COVID-19 or its severity.Methods104 COVID-19 convalescent plasma donors with/without history of hospitalization and 18 blood donors with asymptomatic COVID-19, all were positive for anti-SARS-CoV-2 IgG antibody as well as a group of healthy control including 68 blood donors with negative antibody were subjected to HLA-E genotyping. As a privilege, individuals hadn't been vaccinated against COVID-19 and therefore naturally exposed to the SARS-CoV-2.ResultsThe absence of HLA-E*01:03 allele significantly decreases the odds of susceptibility to SARS-CoV-2 infection [p = 0.044; OR (95 %CI) = 0.530 (0.286 - 0.983)], suggesting that HLA-E*01:01 + HLA-E*01:01 genotype favors more protection against SARS-CoV-2 infection. HLA-E*01:03 + HLA-E*01:03 genotype was also significantly associated with more severe COVID-19 [p = 0.020; 2.606 (1.163 - 5.844) CONCLUSION: Here, our observation about lower susceptibility of HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19 could be clinical evidence in support of some previous studies suggesting that the lower affinity of HLA-E*01:01 to peptides derived from the leader sequence of MHC class Ia may instead shift its binding to virus-derived peptides, which then facilitates target recognition by restricted conventional CD8+ T cells and leads to efficient cytolysis. On the other hand, according to other studies, less reactivity of HLA-E*01:01 with NKG2A abrogates NK cells or T cells inhibition, which may also lead to a greater cytotoxicity against SARS-CoV-2 infected cells compared to HLA-E*01:03. Taken together given HLA-E polymorphisms, the data presented here may be useful in identifying more vulnerable individuals to COVID-19 for better care and management. Especially since along with other risk factors in patients, having HLA-E*01:03 + HLA-E*01:03 genotype may also be associated with the possibility of severe cases of the disease.

Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Dataset Information

HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

Publications

HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

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