Abstract
Background:Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.Methods:We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants.Results:Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10-6).Conclusion:This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk.
Highlights
Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies
Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer
We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer
Summary
We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We utilized genetic variants associated with each risk factor (FI, FG, postchallenge insulin, T2D, and BMI). We included all variants associated with FI [11], T2D [12,13,14,15], FG [11], and BMI [16] at genome-wide statistical significance thresholds (P < 5 x 10–8) in previously published large-scale genome-wide meta-analyses in individuals of European ancestry. In recently published large-scale meta-analyses [17], two (of 19) variants previously included in the insulin secretion score (near DGKB and TFB1M) had an opposite direction of effect to that expected (albeit with statistically nonsignificant associations) and, as such, were excluded from analyses as detailed in Supplementary Table 1 (available online). 18 FI-associated variants, 49 T2D-associated variants, 36 FG-associated variants, 32 BMI-associated variants, and 17 variants associated with early postchallenge insulin secretion [10]
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