Post genome-wide gene-environment interaction study: The effect of genetically driven insulin resistance on breast cancer risk using Mendelian randomization
Year: 2019
Type: article
Abstract: PURPOSE: The role of insulin resistance (IR) in developing postmenopausal breast cancer has not been thoroughly resolved and may be confounded by lifestyle factors such as obesity. We examined whether genetically determined IR is causally associated with breast cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses using individual-level data from our previous meta-analysis of a genome-wide association study (GWAS) (n = 11,109 non-Hispanic white postmenopausal women). Four single-nucleotide polymorphisms were associated with fasting glucose (FG), 2 with fasting insulin (FI), and 6 with homeostatic model assessment-IR (HOMA-IR) but were not associated with obesity. We used this GWAS to employ hazard ratios (HRs) for breast cancer risk by adjusting for potential confounding factors. RESULTS: No direct association was observed between comprising 12 IR genetic instruments and breast cancer risk (HR = 0.93, 95% CI: 0.76-1.14). In phenotype-specific analysis, genetically elevated FG was associated with reduced risk for breast cancer (main contributor of this MR-effect estimate: G6PC2 rs13431652; HR = 0.59, 95% CI: 0.35-0.99). Genetically driven FI and HOMA-IR were not significantly associated. Stratification analyses by body mass index, exercise, and dietary fat intake with combined phenotypes showed that genetically elevated IR was associated with greater breast cancer risk in overall obesity and inactive subgroups (single contributor: MTRR/LOC729506 rs13188458; HR = 2.21, 95% CI: 1.03-4.75). CONCLUSIONS: We found complex evidence for causal association between IR and risk of breast cancer, which may support the potential value of intervention trials to lower IR and reduce breast cancer risk.
Source: PLoS ONE
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,595
Funders: Foundation for the National Institutes of Health, U.S. Department of Health and Human Services, Brigham and Women's Hospital, Ohio State University, Wake Forest University, University of Pittsburgh, MedStar Health Research Institute, National Institutes of Health, University at Buffalo, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Nursing Research
Awards: G1057152193, G1165142596, G1751341341, G1947136479, G2140338431, G2273349799, G2412562481, G2636451769, Insulin-Resistance Genetic and Epigenetic Variants and Their Interactions with Lifestyle Factors in Postmenopausal Breast Cancer, G2973842679, G3255761503, G3545534745, G3796112702, G3868633979, G4021838900, G412187901, G4240450635, G4312823968, G433713863, G4430667546, G4940192625, G5547620395, G5624510383, G614814196, G619791618, G673128162, G6967911674, G8536616440
OpenAlex ID: W2954635194