Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis.
Journal of the National Cancer Institute 2015 ; 107: .
Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK, Barker A, Australian National Endometrial Cancer Study Group (ANECS), Perry JR, Attia J, Dunning AM, Easton DF, Holliday E, Lotta LA, O'Mara T, McEvoy M, Pharoah PD, Scott RJ, Spurdle AB, Langenberg C, Wareham NJ, and Scott RA
DOI : 10.1093/jnci/djv178
PubMed ID : 26134033
PMCID : PMC4572886
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.
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.
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)).
This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk.