Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Abstract

Background The strongest known risk factor for endometrial cancer (EC) is obesity. To determine whether single nucleotide polymorphisms (SNPs) associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with EC risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and EC in 6,609 cases and 37,926 country-matched controls. Methods Logistic regression analysis and fixed-effects meta-analysis were used to test for associations between EC risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for EC was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results The BMIwGRS was significantly associated with EC risk (P=3.4×10−17). Scaling the effect of the BMIwGRS on EC risk by its effect on BMI, the EC odds ratio (OR) per 5kg/m2 of genetically predicted BMI was 2.06 (95% confidence interval(CI)=1.89–2.21), larger than the observed effect of BMI on EC risk (OR=1.55, 95%CI 1.44–1.68, per 5kg/m2). The association attenuated but remained significant after adjusting for BMI (OR=1.22, 95%CI=1.10–1.39,P=5.3×10−4). There was evidence of directional pleiotropy (P=1.5×10−4). BMI SNP rs2075650 was associated with EC at study-wide significance (P<4.0×10−4), independent of BMI. EC was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions BMI, but not WHR, is causally associated with EC risk, with evidence that some BMI-associated SNPs alter EC risk via mechanisms other than measurable BMI. Impact The causal association between BMI SNPs and EC has possible implications for EC risk modeling.

Risk factors for endometrial cancer: An umbrella review of the literature

“…Similarly, the International Agency for Research on Cancer recently deemed adiposity to be causal for endometrial cancer . Furthermore, our findings are in partial agreement with recent Mendelian Randomisation studies, where genetically elevated BMI, but not WHR, was found to be causally associated with endometrial cancer risk . The mechanisms that may underlie the association of obesity with endometrial cancer are not fully characterised but likely include higher oestrogen levels in postmenopausal women, hyperinsulinaemia and a chronic inflammatory state .…”

“…138 Furthermore, our findings are in partial agreement with recent Mendelian Randomisation studies, where genetically elevated BMI, but not WHR, was found to be causally associated with endometrial cancer risk. 139,140 The mechanisms that may underlie the association of obesity with endometrial cancer are not fully characterised but likely include higher oestrogen levels in postmenopausal women, hyperinsulinaemia and a chronic inflammatory state. 4,8,19,141,142 In our review, the evidence for an association between BMI and endometrial cancer was strong for premenopausal cancer, but was highly suggestive for postmenopausal disease due to large between-study heterogeneity, which could be due to a stronger association observed between BMI and endometrial cancer among neverusers than among ever-users of HRT (RR 1.90, 95% CI 1.56-2.30, and RR 1.18, 95% CI 1.07-1.31).…”

BMI and Mortality in UK Biobank: Revised Estimates Using Mendelian Randomization

“…Mendelian randomization (MR) is a well-documented application of instrumental variable (IV) methodology using genetic variants (most commonly, single-nucleotide polymorphisms [SNPs]) as IVs to provide relatively unbiased causal estimates of the effect of an exposure (i.e., BMI) on an outcome (i.e., mortality) (14,15). MR has provided evidence to support a causal effect of higher BMI increasing the risk of cardiovascular diseases (CVDs), diabetes, cardiometabolic traits, and various cancers (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). However, no study has explicitly used MR to explore the causal role of BMI in all-cause and cause-specific mortality.…”

Type 2 diabetes, adiposity and cancer morbidity and mortality risk taking into account competing risk of noncancer deaths in a prospective cohort setting

“…3,4 Mendelian randomization studies point to a causal positive association between body mass index (BMI) and some cancers that have shown consistent associations with adiposity in observational studies. [5][6][7][8][9] The causal pathways for the T2D-cancer association are, however, far from established. It is not clear whether it is the metabolic changes (e.g., hyperglycemia or hyperinsulinemia) associated with T2D that affect cancer risk or whether the association is due to nonbiological factors or potentially shared risk factors for T2D and cancer.…”