Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis

Abstract

Background In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 × 10–4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 × 10–4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 × 10–19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 × 10–6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

World Cancer Research Fund International: Continuous Update Project—systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk

“…Our findings are generally in agreement with those of published umbrella reviews of the literature evidence on physical activity and adiposity with cancer risk [216][217][218], but are opposite to the results of Mendelian randomization (MR) studies. Recent publications from large-sized MR studies reported inverse associations with genetically predicted adiposity for the risk of breast cancer, overall [219] and in premenopausal [220][221][222] and postmenopausal women [220,222], which were not shown in an earlier small study [47]. One possible explanation is that genetically predicted adiposity may be more closely related to early life adiposity than later life adiposity that is largely influenced by the environment.…”

Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

“…Multiple biological mechanisms are hypothesized to mediate the potential beneficial role of physical activity on cancer development. Greater physical activity has been associated with lower circulating levels of insulin and insulin-like growth factors, which promote cellular proliferation in breast and colorectal tissue and have also been linked to development of cancers at these sites [18][19][20][21][22][23] . Higher levels of physical activity have also been associated with lower circulating levels of estradiol, estrone, and higher levels of sex hormone binding globulin [24][25][26] which are strong risk factors for breast cancer development 27,28 .…”

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

“…The number of IVs, variance explained, F statistic, sample size and units are described for the glycaemic exposures. The F statistic was calculated from the number of IVs, variance explained and sample size as described previously (45). The variance explained was only from the IVs utilised in this study (44).…”