Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma Christian M. Lange 1,2,⇑,  , Stéphanie Bibert 3,  , Jean-François Dufour 4 , Cristina Cellerai 5 , Andreas Cerny 6 , Markus H. Heim 7 , Laurent Kaiser 8 , Raffaele Malinverni 9 , Beat Müllhaupt 10 , Francesco Negro 11 , David Semela 12 , Darius Moradpour 1 , Zoltán Kutalik 13,14,  , Pierre-Yves Bochud 3,⇑,  , the Swiss Hepatitis C Cohort Study Group à 1 Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland; 2 Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., D-60590 Frankfurt a.M., Germany; 3 Service of Infectious Diseases, Department of Medicine, University Hospital Lausanne, Lausanne, Switzerland; 4 University Clinic of Visceral Surgery and Medicine, Inselspital, CH-3010 Bern, Switzerland; 5 Division of Immunology and Allergy, Departments of Medicine and of Laboratories, University Hospital Lausanne, CH-1011 Lausanne, Switzerland; 6 Liver Unit, Ospedale Moncucco, CH-6900 Lugano, Switzerland; 7 Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland; 8 HIV-AIDS Unit, Infectious Diseases Service, Geneva University Hospitals, CH-1211 Geneva, Switzerland; 9 Hôpital Neuchâtelois, CH-2000 Neuchâtel, Switzerland; 10 Division of Gastroenterology and Hepatology, University Hospital Zürich, CH-8091 Zürich, Switzerland; 11 Division of Gastroenterology and Hepatology, University Hospital Geneva, CH-1211 Geneva, Switzerland; 12 Division of Gastroenterology, Kantonsspital St. Gallen, CH-9000 St. Gallen, Switzerland; 13 Department of Medical Genetics, University of Lausanne, Lausanne, CH-1011 Lausanne, Switzerland; 14 Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland Background & Aims: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identi- fied 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 calcu- lated both in the Japanese and European populations (HapMap3: CEU and JPT). Results: To our surprise, the minor allele A of rs2596542 in prox- imity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse associa- tion 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 origi- nally identified SNPs. Conclusions: Our data confirms the MICA/HCP5 region as suscep- tibility 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 eth- nicities in order to fine map GWAS signals. Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction Chronic hepatitis C is associated with significant morbidity, resulting in liver cirrhosis and its complications in a considerable proportion of infected individuals [1]. Due to the changing demo- graphics of hepatitis C virus (HCV)-infected individuals in the western world, a dramatic increase of cases with advanced liver cirrhosis and hepatocellular carcinoma (HCC) is expected for the near future [1,2]. Therefore, the identification of risk factors for the progression to HCC is crucial for an improved clinical management of patients with chronic hepatitis C [1,3]. Recently, two independent genome-wide association studies (GWAS) have been performed to identify novel susceptibility loci for HCC Journal of Hepatology 2013 vol. 59 j 504–509 Keywords: MICA; Hepatocellular carcinoma; Chronic hepatitis C; GWAS; Liver cancer. Received 29 December 2012; received in revised form 16 April 2013; accepted 24 April 2013; available online 9 May 2013 ⇑ Corresponding authors. Addresses: Klinikum der J. W. Goethe-Universität Frankfurt a.M., Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt a.M., Germany. Tel.: +49 69 6301 87838; fax: +49 69 6301 6448 (C.M. Lange). Service of Infectious Diseases, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. Tel.: +41 21 314 4379; fax: +41 21 314 1033 (P.-Y. Bochud). E-mail addresses: Christian.Lange@kgu.de (C.M. Lange), Pierre-Yves.Bochud@ chuv.ch (P.-Y. Bochud).   These authors contributed equally to this work. à See Addendum. Abbreviations: GWAS, genome-wide association study; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCP5, HLA class I histocompatibility antigen co- ntaining P5; HCV, hepatitis C virus; LD, linkage disequilibrium; MICA, MHC class I polypeptide-related sequence A gene; SCCS, Swiss Hepatitis C Cohort Study; SNP, single nucleotide polymorphism ; SVR, sustained virologic response. Research Article