Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection.
Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.
['Tao|Jingjing|J|', 'Su|Kunkai|K|', 'Yu|Chengbo|C|', 'Liu|Xiaoli|X|', 'Wu|Wei|W|', 'Xu|Wei|W|', 'Jiang|Bingxun|B|', 'Luo|Rui|R|', 'Yao|Jian|J|', 'Zhou|Jiawei|J|', 'Zhan|Yan|Y|', 'Ye|Chao|C|', 'Yuan|Wenji|W|', 'Jiang|Xianzhong|X|', 'Cui|Wenyan|W|', 'Li|Ming D|MD|', 'Li|Lianjuan|L|']
D020413:3' Untranslated Regions D000328:Adult D016022:Case-Control Studies D002874:Chromosome Mapping D002896:Chromosomes, Human, Pair 6 D005260:Female D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D005838:Genotype D006682:HLA-DP Antigens D059868:HLA-DP beta-Chains D006683:HLA-DQ Antigens D006239:Haplotypes D006515:Hepatitis B virus D019694:Hepatitis B, Chronic D006579:Heterozygote D006801:Humans D015810:Linkage Disequilibrium D008103:Liver Cirrhosis D008297:Male D008875:Middle Aged D005810:Multigene Family D020641:Polymorphism, Single Nucleotide D011786:Quality Control
HLA-DP SNPs Association analysis Conditional analysis HLA-DPB HLA-DQ Hepatitis B virus infection Host susceptibility