Abstract
BackgroundPrevious gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.MethodsAnalyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.ResultsNoteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10–4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10–5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.ConclusionsOverall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.
Highlights
Breast cancer is a complex disease with both environmental and genetic factors contributing to risk
The associations of the environmental risk factors with breast cancer risk were as expected in the population-based studies; in brief, age at menarche, being parous, number of full-term pregnancies, ever breastfeeding, cumulative duration of breastfeeding and premenopausal body mass index (BMI) were negatively associated with breast cancer risk, whereas age at first full-term pregnancy, ever use of oral contraceptives, postmenopausal BMI, current use of estrogen-progesterone therapy (EPT), adult height, current smoking and cumulative alcohol consumption were all positively associated with breast cancer risk (Table 1; Supplementary Figures 1–3, available as Supplementary data at IJE online)
The minor allele of single nucleotide polymorphisms (SNPs) rs4442975 was associated with a stronger reduced risk of breast cancer for current users of EPT (ORmeta 1⁄4 0.74, 95% confidence interval (CI) 1⁄4 0.690.80) than for never users of menopausal hormonal therapy (MHT) (ORmeta 1⁄4 0.87, 95% CI 1⁄4 0.84-0.90) (Figure 1A)
Summary
Breast cancer is a complex disease with both environmental and genetic factors contributing to risk. Estimation of any combined effect of genetic and environmental factors, including gene-environment (G x E) interactions, is considered to possibly improve breast cancer risk prediction, and identification of women at high risk for targeted prevention. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int 1⁄4 0.85 (0.78-0.93), Pint 1⁄4 2.8 x 10–4] and overall breast cancer [ORint 1⁄4 0.85 (0.78-0.92), Pint 1⁄4 7.4 x 10–5) in current users of estrogen-progesterone therapy compared with non-users This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 1⁄4 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint 1⁄4 0.004). Conclusions: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors
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