James Yarmolinsky, Ph.D., Research Fellow at the University of Bristol. In this video, he speaks about Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
In high-income countries, endometrial cancer is the most frequent gynaecological malignancy. Elevated BMI is a known modifiable risk factor for this condition, and it is thought to have a greater impact on endometrial cancer risk than any other cancer site. The molecular processes behind this relationship, however, remain unknown. Mendelian randomization (MR) was utilized to investigate the involvement of 14 molecular risk variables (hormonal, metabolic, and inflammatory indicators) in endometrial cancer risk. Using multivariable MR, we then assessed and quantified the potential mediating impact of these molecular characteristics in the link between BMI and endometrial cancer.
By identifying single-nucleotide polymorphisms (SNPs) reliably related (P 5.0 108) with each relevant risk factor in prior genome-wide association studies, genetic instruments to proxy 14 molecular risk factors and BMI were created (GWAS). A GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), and UK Biobank yielded summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls). SNPs were incorporated into multi-allelic models, and inverse-variance weighted random-effects models were used to create odds ratios (ORs) and 95 percent confidence intervals (CIs). The molecular risk variables' mediating roles in the association between BMI and endometrial cancer were then assessed using multivariable MR.
There was strong evidence in MR analyses that BMI (OR per standard deviation (SD) increase 1.88, 95 percent CI 1.69 to 2.09, P = 3.87 1031), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95 percent CI 1.43 to 1.88, P = 1.71 1012), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95 percent CI 1.29 to 1.65, P = 3.48 109), fast There was also evidence that total blood cholesterol (OR per mg/dL increase 0.90, 95 percent CI 0.81 to 1.00, P = 4.01 102) influenced endometrial cancer risk. Fasting insulin (19 percent total effect mediated, 95 percent CI 5 to 34 percent, P = 9.17 103), bioavailable testosterone (15 percent mediated, 95 percent CI 10 to 20 percent, P = 1.43 108) and SHBG (7 percent mediated, 95 percent CI 1 to 12 percent, P = 1.81 102) were found to play a mediating role in the relationship between BMI and endometrial cancer risk.
Our thorough MR analysis sheds light on putative causative processes relating BMI to endometrial cancer risk and proposes that targeting insulinemic and hormonal characteristics as a feasible method for endometrial cancer prevention.