Genome-Wide Association Study Of Primary Biliary Cholangitis In The Han Chinese Population

Objective To identify the susceptibility genes of primary biliary cholangitis(PBC)in the Han Chinese population,compare the similarities and differences of PBC susceptibility genes between the han population and other populations,understand the molecular genetic mechanism of PBC.Methods A large scale case-control genome wide association study(GWAS),including 1127 PBC subjects and 4074 controls cohort,was performed by the Human Omni Zhong Hua-8 beadchip,and a replication study,including 907 PBC cases and 2127 controls,was performed by Sequenom Mass Array platform,the final combined analysis included 2029 PBC cases and 6163 controls.IL21/IL21 R immunohistochemical analysis was performed on liver tissue slides of PBC patients by Leica automatic immunohistochemical system.Results 179 SNPs in the HLA region and 39 SNPs in 8 non-HLA loci were exceeded genome-wide significance in the discovery stage.2 SNPs from the HLA region and 32 SNPs from24 non-HLA loci were selected for replication.The most significant association was observed with rs9268644,a variant in HLA-DRA locus.Eight previously identified PBC susceptibility loci in ignaling and Japanese,also confirmed in our study.Among the non-HLA loci,the strongest association was observed in rs4979467,a SNP in the TNFSF15-TNFSF8 locus.We identified variants in IL21,IL21 R,CD28/CTLA4/ICOS,CD58,ARID3 A and IL16 as novel PBC risk loci.Significantly elevated levels of expression of IL21 and IL21 R was observed in the livers of PBC patients.The numbers of IL21+ cells and IL21R+cells were positively correlated with inflammation severity and hepatic fibrosis stages.Conclusions This is the first report of a large scale GWAS of PBC in the Han Chinese population and has identified six new PBC susceptibility loci.Our study supports the hypothesis that the IL21 signalling pathway and Tfh cells are involved in PBC pathogenesis.Our results also draw attention to the importance of T-cell costimulatory signaling in PBC and advance our understanding of PBC as a disease of immune deregulation.