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

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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Hepatocellular / etiology*
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / immunology
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Hepatitis C, Chronic / complications*
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / immunology
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / immunology
  • Major Histocompatibility Complex / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • RNA, Long Noncoding
  • RNA, Untranslated
  • Switzerland

Substances

  • HCP5 long noncoding RNA, human
  • Histocompatibility Antigens Class I
  • MHC class I-related chain A
  • RNA, Long Noncoding
  • RNA, Untranslated