Abstract
BackgroundCirculating glycemic traits (GTs) have been considered a risk factor for breast cancer, but studies using GT-associated genetic variants as an instrumental variable are limited and inconclusive.MethodsOur Mendelian Randomization analysis used the most recent genome-wide datasets focusing on European women.ResultsOf 44 single-nucleotide polymorphisms (SNPs) with GTs, 38 fasting-glucose and 6 fasting-insulin SNPs showed heterogeneous associations with breast cancer, without significant directional pleiotropy observed.ConclusionOur findings indicate a null association between genetically determined GTs and breast cancer risk among European women. Our findings may contribute to more complete characterizing of metabolic pathways in GTs and breast cancer.
Highlights
Previous studies for circulating glycemic traits (GTs), including fasting glucose (FG) and insulin (FI) concentrations, have shown inconsistent associations with breast cancer development (Gunter et al, 2009; Sieri et al, 2012; Boyle et al, 2013; Hernandez et al, 2014)
CI, confidence interval; CGEMS, Cancer Genetic Markers of Susceptibility Breast Cancer Genome-wide Association (GWA) Study; FG, fasting glucose; FI, fasting insulin; GEEA, generalized estimating equation regression adjusted for age; GEEAB, GEEA, adjusted for body mass index; GM, glucose metabolism; Mendelian Randomization (MR), Mendelian randomization; OR, odds ratio; single-nucleotide polymorphisms (SNPs), single–nucleotide polymorphism; T2DM, type 2 diabetes; WHR, waist-to-hip ratio. †Phat was estimated via Cochran’s Q; by correcting multiple comparisons, the MR results for the following sets of SNPs were statistically heterogeneous: FG-OncoArray; FG-OncoArray*; FG-OncoArray-T2DM¥; FG-OncoArray-T2DM¥*; FG-Pooled MR; and FI-OncoArray-WHR¥. *A subset of the GM-SNPs that are statistically associated with breast cancer (p < 0.05) was included in the analysis. ¥GM-SNPs excluding top GWA-SNPs associated with T2DM or WHR were analyzed to reduce the pleiotropic effect from T2DM or WHR, respectively
After excluding top GWA-SNPs associated with type 2 diabetes and visceral obesity, the directions of the associations between GTs and breast cancer were changed in OncoArray but not in ATLAS-CGEMS
Summary
Our findings indicate a null association between genetically determined GTs and breast cancer risk among European women.
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