Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma.
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.


CONCLUSIONS
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.
Peters
Ulrike
U
Public Health Science, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA 98109-1024, USA. upeters@fhcrc.org
Chatterjee
Nilanjan
N
Hayes
Richard B
RB
Schoen
Robert E
RE
Wang
Yinghui
Y
Chanock
Stephen J
SJ
Foster
Charles B
CB
D000236:Adenoma / Q000201:enzymology* / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012643:Selenium; D051149:Selenoprotein P / Q000235:genetics; D011795:Surveys and Questionnaires; D054481:Thioredoxin Reductase 1 / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
D051149:Selenoprotein P; C117436:GPX2 protein, human; C486484:GPX3 protein, human; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D012643:Selenium; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human