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Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection

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Abstract

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.

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Acknowledgments

We thank all the volunteers who participated in this study. We also thank the many clinical research staff and clinicians in the First Affiliated Hospital of Zhejiang University School of Medicine for helping us to recruit these participants.

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Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China

    Jingjing Tao, Kunkai Su, Chengbo Yu, Xiaoli Liu, Wei Wu, Wei Xu, Bingxun Jiang, Rui Luo, Jian Yao, Jiawei Zhou, Yan Zhan, Chao Ye, Wenji Yuan, Xianzhong Jiang, Wenyan Cui, Ming D. Li & Lianjuan Li

  2. Department of Psychiatry and Neurobehavioral Science, University of Virginia, 450 Ray C Hunt Drive, Charlottesville, VA, 22903, USA

    Ming D. Li

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  1. Jingjing Tao
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  16. Ming D. Li
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  17. Lianjuan Li
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Correspondence to Ming D. Li or Lianjuan Li.

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Funding

This study was in part supported by the National Science and Technology Major Project (No. 2012ZX10002004) and the Chinese High Technology Research and Development program (No. 2012AA020204).

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The authors declare no conflict of interest related to this paper.

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Tao, J., Su, K., Yu, C. et al. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection. Amino Acids 47, 2623–2634 (2015). https://doi.org/10.1007/s00726-015-2054-6

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