title: Glutathione peroxidase tagSNPs: associations with rectal cancer but not with colon cancer.
abstract: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that reduce and, thus, detoxify hydrogen peroxide and a wide variety of lipid hydroperoxides. We investigated tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis from adenoma to cancer. A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r(2) ≥ 0.90, MAF ≥ 4%) identified 21 tagSNPs. We used an identical Illumina platform to genotype GPX SNPs in three population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal component analysis (PCA); multiple logistic regression was used for single SNPs. Analyses were adjusted for age, sex, and study center and restricted to non-Hispanic white participants. Analyses of cancer endpoints were stratified by molecular subtypes. Without correction for multiple testing, one polymorphism in GPX2 and three polymorphisms in GPX3 were associated with a significant risk reduction for rectal cancer at α = 0.05, specifically for rectal cancers with TP53 mutations. The associations regarding the three polymorphisms in GPX3 remained statistically significant after adjustment for multiple comparisons. The PCA confirmed an overall association of GPX3 with rectal cancer (P = 0.03). No other statistically significant associations were observed. Our data provide preliminary evidence that genetic variability in GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for differences in underlying pathogenetic mechanisms for colon and rectal cancer.
authors.affiliation: Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Haug
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.forename: Liren
authors.initials: L
authors.lastname: Xiao
authors.forename: Karen
authors.initials: K
authors.lastname: Curtin
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kulmacz
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Lisel
authors.initials: L
authors.lastname: Koepl
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D011795:Surveys and Questionnaires
chemical_list: D014408:Biomarkers, Tumor; D005979:Glutathione Peroxidase