Abstract
BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Highlights
The association between body mass index (BMI) and breast cancer risk has been extensively investigated in observational epidemiologic studies
A modest positive association has been reported between BMI and postmenopausal breast cancer risk [1,3,8], and this association was primarily limited to women who did not use postmenopausal hormone therapy (HT) [2,9,10] or women diagnosed with estrogen receptor (ER)-positive breast cancer [10]
Utilizing data from two large consortia, we found in this large Mendelian randomization (MR) study a consistent inverse association between BMI predicted by genome-wide association studies (GWAS)-identified genetic variants and premenopausal breast cancer risk in all subgroups examined, which is qualitatively consistent with the majority of published epidemiologic studies using measured BMI, our predicted association, a 46% reduction in risk per 5 kg/m2 increase in BMI, is larger than that estimated in observational studies using measured BMI [1,3,5,8,29]
Summary
The association between body mass index (BMI) and breast cancer risk has been extensively investigated in observational epidemiologic studies. Overweight women have been found to have higher estrogen levels than normal weight women, providing a possible explanation for positive associations observed between BMI and breast cancer risk in postmenopausal women These postulated explanations are biologically plausible for the different associations observed between measured BMI and breast cancer risk in pre-and postmenopausal women, it remains unclear whether BMI is causally associated with breast cancer risk or serves as a surrogate measure for other risk factors. Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women It is unclear whether this association is mediated through shared genetic or environmental factors
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