Abstract
Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10−18) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.
Highlights
Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations
In the regression analysis using three representative SNPs located in both HLA-DP and HLA-DQ regions as covariates, a number of SNPs located around the SNPs showed weakened (Supplementary Fig. 2)
These results indicated that SNPs in HLA-DP and HLA-DQ regions were in strong linkage disequilibrium (LD) each other
Summary
To investigate the relationship between HLA-DP variants (rs2395309 for HLA-DPA1 and rs9277496 for HLA-DPB1) and the HLA-DQB1 variant (rs9368737) and CHB susceptibility, we performed logistic regression analysis using the three associated SNPs as covariates. Among the twenty-five haplotypes of HLA-A-C-B-DRB1-DQB1-DPB1 whose frequencies were over 0.5% in either of two groups (i.e. HBV patients and healthy controls), the most frequent haplotype showed the strongest association with CHB susceptibility in the studied individuals (OR = 1.81; 95%CI = 1.47–2.22, P = 1.03 × 10−8 for HLA-A*24:02-C*12:02-B*52:01DRB1*15:02-DQB1*06:01-DPB1*09:01). Haplotype analysis of HLA class I genes and HLA class II genes showed a total of twenty-three haplotypes and twenty-five haplotypes, respectively, whose frequencies were over 1.0% in either of the two groups Among these haplotypes, the haplotype harboring DQB1*06:01 showed up with the highest frequency in the studied individuals, and had a significant association with CHB susceptibility (OR = 1.91; 95%CI = 1.61–2.28, P = 1.13 × 10−13 for HLA-DRB1*15:02-DQB1*06:01-DPB1*09:01). The association of the remaining two alleles (DPB1*09:01 and *04:01) had come from LD with HLA-DR-DQ haplotypes (i.e. DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively) These observations provide an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in this particular genomic region. The impact of disease-associated HLA alleles or haplotypes on clinical diagnosis is small, further analysis to identify new host factors behind HLA genes, viral factors and clinical features may proceed effectively by selecting individuals who have the disease-associated HLA class II alleles
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