Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma

Lange, Christian M.; Bibert, Stéphanie; Dufour, Jean-François; Cellerai, Cristina; Cerny, Andreas; Heim, Markus H.; Kaiser, Laurent; Malinverni, Raffaele; Müllhaupt, Beat; Negro, Francesco; Semela, David; Moradpour, Darius; Kutalik, Zoltán; Bochud, Pierre-Yves (2013). Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma. Journal of hepatology, 59(3), pp. 504-509. Elsevier 10.1016/j.jhep.2013.04.032

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BACKGROUND & AIMS:

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 of HCC development in the Caucasian population as well.

METHODS:

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 European populations (HapMap3: CEU and JPT).

RESULTS:

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 of 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.

CONCLUSIONS:

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.

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