Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer
Menée par une méthode de randomisation mendélienne à partir de données portant sur 6 6019 patientes atteintes d'un cancer de l'endomètre et sur 37 926 témoins, cette étude évalue l'association entre 77 polymorphismes à simple nucléotide de gènes liés à l'indice de masse corporelle, 47 polymorphismes de gènes liés au rapport taille-hanches, et le risque de la maladie
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=3.4x10-17). 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=5.3x10-4). There was evidence of directional pleiotropy (P=1.5x10-4). BMI SNP rs2075650 was associated with EC at study-wide significance (P<4.0x10-4), 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. -
Cancer Epidemiology Biomarkers & Prevention , résumé, 2016