title: Genome-wide investigation of gene-environment interactions in colorectal cancer.
abstract: Colorectal cancer (CRC), one of the most frequent neoplasias worldwide, has both genetic and environmental causes. As yet, however, gene-environment (G × E) interactions in CRC have been studied mostly for a small number of candidate genes only. Therefore, we investigated the possible interaction, in CRC etiology, between single-nucleotide polymorphisms (SNPs) on the one hand, and overweight, smoking and alcohol consumption on the other, at a genome-wide level. To this end, we adopted a two-tiered approach comprising a case-only screening stage I (314 cases) and a case-control validation stage II (259 cases, 1,002 controls). Interactions with the smallest p value in stage I were verified in stage II using multiple logistic regression analysis adjusted for sex and age. In addition, we specifically studied known CRC-associated SNPs for possible G × E interactions. Upon adjustment for sex and age, and after allowing for multiple testing, however, only a single SNP (rs1944511) was found to be involved in a statistically significant interaction, namely with overweight (multiplicity-corrected p = 0.042 in stage II). Several other G × E interactions were nominally significant but failed correction for multiple testing, including a previously reported interaction between rs9929218 and alcohol consumption that also emerged in our candidate SNP study (nominal p = 0.008). Notably, none of the interactions identified in our genome-wide analysis was with a previously reported CRC-associated SNP. Our study therefore highlights the potential of an "agnostic" genome-wide approach to G × E analysis.
authors.affiliation: Section of Epidemiology, Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Siegert
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Witigo
authors.initials: W
authors.lastname: von Schönfels
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.forename: Jesús
authors.initials: J
authors.lastname: Lascorz
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Ute
authors.initials: U
authors.lastname: Nöthlings
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult