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J Hepatol. 2013 Sep;59(3):504-9. doi: 10.1016/j.jhep.2013.04.032. Epub 2013 May 9.

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

Author information

1
Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland. Christian.Lange@kgu.de

Abstract

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.

KEYWORDS:

Chronic hepatitis C; GWAS; HBV; HCC; HCP5; HCV; HLA class I histocompatibility antigen containing P5; Hepatocellular carcinoma; LD; Liver cancer; MHC class I polypeptide-related sequence A gene; MICA; SCCS; SNP; SVR; Swiss Hepatitis C Cohort Study; genome-wide association study; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; linkage disequilibrium; single nucleotide polymorphism; sustained virologic response

PMID:
23665287
DOI:
10.1016/j.jhep.2013.04.032
[Indexed for MEDLINE]

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