Abstract
BackgroundGerm-line mutations in genes such as BRCA1, BRCA2, and ATM can cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population, and account for little of the incidence of sporadic breast cancer in the general population. Therefore, research has been focused on examining associations between common polymorphisms and breast cancer risk. To date, few associations have been described. This has led to the hypothesis that breast cancer is a complex disease, whereby a constellation of very low penetrance alleles need to be carried to present a risk phenotype. Polymorphisms in the manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX-1) genes have been proposed as low penetrance alleles, and have not been clearly associated with breast cancer. We investigated whether variants at both polymorphisms, while not independently associated with breast cancer risk, could influence breast cancer risk when considered together.MethodsA case-control study nested within the Nurses' Health Study was performed comparing 1262 women diagnosed with breast cancer to 1533 disease free women. The MnSOD (Val16Ala, rs1799725) and GPX-1 (Pro198Leu, rs1050450) were genotyped via TaqMan assay. Disease risk was evaluated using logistic regression.ResultsWhile neither allele alone shows any change in breast cancer risk, an increase in the risk of breast cancer (OR 1.87, 95% CI 1.09 – 3.19) is observed in individuals who carry both the Ala16Ala genotype of MnSOD and the Leu198Leu genotype of GPX-1.ConclusionPolymorphisms in the GPX-1 and MnSOD genes are associated with an increased risk of breast cancer.
Highlights
Germ-line mutations in genes such as BRCA1, BRCA2, and ATM can cause a substantial increase in risk of breast cancer
Polymorphisms in the GPX-1 and manganese superoxide dismutase (MnSOD) genes are associated with an increased risk of breast cancer
Few polymorphisms have shown statistically significant associations with breast cancer risk to date. One explanation for this lack of association could be that common polymorphisms do not have a large enough effect on the function of any particular gene to be responsible for cancer development alone
Summary
Genotyping assays for the MnSOD (Val16Ala, rs1799725) and GPX-1 (Pro198Leu, rs1050450) polymorphisms were performed by the 5' nuclease assay (TaqMan) on the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). Our study included a total of 1262 incident breast cancer cases diagnosed after blood draw up to June 1, 2000, and 1533 matched controls, all drawn from 32,826 women in the Nurses' Health Study who gave a blood sample in 1989–90. Internal blinded quality control samples (49 sets of replicate samples, including from 2 to 9 replicates) showed 100% concordance. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, controlling for matching factors, age at menopause, age at menarche, age at first birth and parity, body mass index at age 18, weight gain since age 18, history of benign breast disease, and family history of breast cancer using PROC LOGISTIC. This study was approved by the Institutional Review Board of Brigham and Women's Hospital (protocol # 1999-P-001718)
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