서강대학교

초록/요약

Hepatitis B infection is a serious risk factor for chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) have identified important genetic factors associated with CHB risk. A GWAS on a Korean population identified TCF19 and EHMT2 as susceptibility genes for CHB (P = 4.2×10-9 at TCF19 rs1419881 and P = 2.0×10-9 at EHMT2 rs652888). Each SNP might not be the only causal variant in each gene, and other causal variants may exist in a close site that may be more strongly associated with CHB risk than the variants identified in the initial GWAS. The present study follows up a previous GWAS by conducting fine-mapping association analyses to identify putative additional causal variants for CHB risk. Genes that include the SNP showing the most significant association signal in the initial GWAS (TCF19-OCT4 and EHMT2 genomic region) were analyzed. In total, 44 SNPs (14 of TCF19; 19 of OCT4; 11 of EHMT2) were selected and genotyped from 1,046 CHB patients and 2,856 healthy controls. A subsequent statistical analysis revealed that the strongest genetic effects on CHB risk were found with OCT4 rs1265163 and EHMT2 rs35875104 with an independent effect with previously known CHB risk loci. Genetic risk scores were calculated to visualize the combined genetic effects of all known CHB-associated loci, including OCT4 rs1265163 and EHMT2 rs35875104, which were additionally identified in this study. Additional MHC region-specific imputation analysis was performed to discover the disease-driving gene and genetic loci in the MHC region based on the initial GWAS data. The most significant association with CHB risk was found at HLA-DRB1 amino acid position 71 and the HLA-DRB1*13 variant (P < 5.0×10-8) with an independent effect with previously known CHB risk loci. This follow-up study identified a possible causal genetic variant associated with CHB risk, and our findings may prove to be useful for understanding the genetic susceptibility to CHB in Korean population.