Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland; Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., D-60590 Frankfurt a.M., Germany. Electronic address: firstname.lastname@example.org.
BACKGROUND AND AIM:
Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive for HCC development in the Caucasian population as well.
An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese- and the European populations (HapMap3: CEU and JPT).
To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor for HCV-related HCC in the SCCS (univariable P=0.027; multivariable P=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs.
Our data confirms the MICA / HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine-map GWAS signals.