Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 6, Pages 1225-1232Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw003
Keywords
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Funding
- National Science Foundation for Distinguished Young Scholars of China [81225020]
- National Key Basic Research Program For Youth [2013CB911400]
- National Program for Support of Top-notch Young Professionals, the National Major ST Projects [2009ZX10004-904, 2011ZX10004-902, 2013ZX10004-905]
- Foundation for the Program for New Century Excellent Talents in University [NCET-10-0178]
- Foundation for the Author of National Excellent Doctoral Dissertation [201081]
- Jiangsu Specially-appointed Professor Project the National Natural Science Foundation of China [31100895]
- Outstanding Young Scholar Project of Fudan University
- Jiangsu Province Clinical Science and Technology Projects [BL2012008]
- Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)
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Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DP beta 1 amino acid positions 84-87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 x 10(-8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 x 10(-7)). The HLA-DR beta 1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 x 10(-9); OR = 0.28, P = 6.27 x 10(-7), respectively). HLA-DP beta 1 positions 84-87 and HLA-DR beta 1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain similar to 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by knowngenetic variations. We fine mapped theMHCregion and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies.
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