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Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis
Kevin T Nead1, Stephen J Sharp1, Deborah J Thompson1
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK (KTN, SJS, AB, JRBP, LAL, CL, NJW, RAS); Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (KTN); Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (DJT, DFE, PDPP); Queensland Institute of Medical Research, Brisbane, Australia (JNP, ANECS, TO, ABS); University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge, UK (DBS, RKS); Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia (JA, EH, RJS); Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia (JA, MM); Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (AMD, DFE, PDPP); Centre for Information Based Medicine, School of Medicine and Public Health, University of Newcastle, Australia (EH, RJS).
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.
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