title: Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility.
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.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden ; Ludwig Institute for Cancer Research - Stockholm branch, Stockholm, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Picelli
authors.forename: Justo
authors.initials: J
authors.lastname: Lorenzo Bermejo
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Ceres
authors.initials: C
authors.lastname: Fernández-Rozadilla
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Heiko
authors.initials: H
authors.lastname: Müller
authors.forename: Bente A
authors.initials: BA
authors.lastname: Talseth-Palmer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stibbard
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Carmela
authors.initials: C
authors.lastname: Nici
authors.forename: Silvia
authors.initials: S
authors.lastname: Veneroni
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Susan M
authors.initials: SM
authors.lastname: Farrington
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Juul
authors.initials: J
authors.lastname: Wijnen
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
mesh_terms: D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D053843:DNA Mismatch Repair; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
references.citation: Lancet. 2003 Jul 5;362(9377):39-41
references.pmid: 12853198
references.citation: J Exp Clin Cancer Res. 2008 Sep 30;27:49
references.pmid: 18823566
references.citation: Hum Mutat. 2000;15(1):7-12
references.pmid: 10612815
references.citation: Mutagenesis. 2012 Mar;27(2):143-51
references.pmid: 22294761
references.citation: N Engl J Med. 2000 Jul 13;343(2):78-85
references.pmid: 10891514
references.citation: Cancer Sci. 2008 Feb;99(2):355-60
references.pmid: 18271935
references.citation: Nature. 2007 Jun 21;447(7147):941-50
references.pmid: 17581577
references.citation: Nat Rev Genet. 2009 May;10(5):318-29
references.pmid: 19373277
references.citation: Nat Genet. 2002 Feb;30(2):227-32
references.pmid: 11818965
references.citation: Nat Genet. 2010 Nov;42(11):973-7
references.pmid: 20972440
references.citation: DNA Repair (Amst). 2007 Mar 1;6(3):274-9
references.pmid: 17161978
references.citation: J Mol Biol. 2010 Oct 29;403(3):351-70
references.pmid: 20816984
references.citation: Br J Cancer. 2010 Jan 19;102(2):447-54
references.pmid: 19920828
references.citation: N Engl J Med. 2003 Feb 27;348(9):791-9
references.pmid: 12606733
references.citation: Clin Genet. 2008 Jun;73(6):545-53
references.pmid: 18422726
references.citation: Eur J Cancer. 2010 Apr;46(6):1041-8
references.pmid: 20149637
references.citation: Chem Res Toxicol. 2006 Apr;19(4):491-505
references.pmid: 16608160
references.citation: Hum Mutat. 2003 Sep;22(3):181-2
references.pmid: 12938082
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):356-61
references.pmid: 17200375
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:239-67
references.pmid: 14744246
references.citation: Hum Mutat. 2010 Nov;31(11):1205-15
references.pmid: 20725929