title: Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland. Christian.Lange@kgu.de
authors.forename: Christian M
authors.initials: CM
authors.lastname: Lange
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bibert
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Cristina
authors.initials: C
authors.lastname: Cellerai
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Laurent
authors.initials: L
authors.lastname: Kaiser
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D013557:Switzerland; D044465:White People / Q000235:genetics
chemical_list: C080521:HCP5 long noncoding RNA, human; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated
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