Meta-Analysis of Mismatch Repair Polymorphisms within the Cogent Consortium for Colorectal Cancer Susceptibility

Members of the EPICOLON Consortium (Gastrointestinal Oncology Group of the Spanish Gastroenterological Association):, Simone Picelli, Justo Lorenzo Bermejo, Jenny Chang-Claude, Michael Hoffmeister, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Alessio Naccarati, Barbara Pardini, Ludmila Vodickova, Heiko Müller, Bente A Talseth-Palmer, Geoffrey Stibbard, Paolo Peterlongo, Carmela Nici, Silvia Veneroni, Li Li, Graham CaseyAlbert Tenesa, Susan M Farrington, Ian Tomlinson, Victor Moreno, Tom van Wezel, Juul Wijnen, Malcolm Dunlop, Paolo Radice, Rodney J Scott, Pavel Vodicka, Clara Ruiz-Ponte, Hermann Brenner, Stephan Buch, Henry Völzke, Jochen Hampe, Clemens Schafmayer, Annika Lindblom

Research output: Contribution to journalArticlepeer-review

Abstract

In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.
Original languageEnglish
Article numbere72091
Number of pages6
JournalPLoS ONE
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 2013

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