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

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Public Health Science, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA 98109-1024, USA. upeters@fhcrc.org

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    Source

    MeSH

    Adenoma
    Aged
    Case-Control Studies
    Colorectal Neoplasms
    Genetic Variation
    Genotype
    Glutathione Peroxidase
    Haplotypes
    Humans
    Logistic Models
    Middle Aged
    Polymorphism, Single Nucleotide
    Risk
    Selenium
    Selenoprotein P
    Surveys and Questionnaires
    Thioredoxin Reductase 1

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    18483336

    Citation

    Peters, Ulrike, et al. "Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, vol. 17, no. 5, 2008, pp. 1144-54.
    Peters U, Chatterjee N, Hayes RB, et al. Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1144-54.
    Peters, U., Chatterjee, N., Hayes, R. B., Schoen, R. E., Wang, Y., Chanock, S. J., & Foster, C. B. (2008). Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, 17(5), pp. 1144-54. doi:10.1158/1055-9965.EPI-07-2947.
    Peters U, et al. Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1144-54. PubMed PMID: 18483336.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma. AU - Peters,Ulrike, AU - Chatterjee,Nilanjan, AU - Hayes,Richard B, AU - Schoen,Robert E, AU - Wang,Yinghui, AU - Chanock,Stephen J, AU - Foster,Charles B, PY - 2008/5/17/pubmed PY - 2008/10/1/medline PY - 2008/5/17/entrez SP - 1144 EP - 54 JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology JO - Cancer Epidemiol. Biomarkers Prev. VL - 17 IS - 5 N2 - 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. SN - 1055-9965 UR - https://www.unboundmedicine.com/medline/citation/18483336/Variation_in_the_selenoenzyme_genes_and_risk_of_advanced_distal_colorectal_adenoma_ L2 - http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18483336 DB - PRIME DP - Unbound Medicine ER -