||BACKGROUND: Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor. METHODS: Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes. RESULTS: Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5' region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3' region of SEPP1, which is overlapping with the promoter region of an antisense transcript, were significantly associated with adenoma risk: homozygotes at two SEPP1 loci (31,174 bp 3' of STP A>G and 43,881 bp 3' of STP G>A) were associated with increased adenoma risk [odds ratio (OR), 1.48; 95% confidence interval (95% CI), 1.00-2.19 and OR, 1.53; 95% CI, 1.05-2.22, respectively] and the variant SEPP1 44,321 bp 3' of STP C>T was associated with a reduced adenoma risk (CT versus CC OR, 0.85; 95% CI, 0.63-1.15). Furthermore, we observed a significant 80% reduction for advanced colorectal adenoma risk for carriers of the variant allele at TXNRD1 IVS1-181C>G (OR, 0.20; 95% CI, 0.07-0.55; P trend = 0.004). Consistent with the individual SNP results, we observed a significant overall association with adenoma risk for SEPP1 and TXNRD1 (global P = 0.02 and 0.008, respectively) but not for the four GPX genes. CONCLUSION: Our study suggests that genetic variants at or near the SEPP1 and TXNRD1 loci may be associated with advanced colorectal adenoma. As this is the first study to comprehensively investigate this hypothesis, confirmation in independent study populations is needed.