Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese

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.