Use of anthropometric and genetic data to study body fat mass and distribution with cancer risk in European-ancestry populations

Abstract

General obesity, measured by BMI, have been linked to increased incidence and mortality of certain cancer. However, BMI does not account for body composition and could not differentiate between muscle mass and fat. I conducted the first and largest prospective study using UK Biobank data to investigate the associations of body fat mass/distribution with total and major cause-specific mortality and incidence of site-specific cancers, and I found waist-to-hip ratio (WHR) and whole body fat mass confer additional risk of multiple disease outcomes beyond the level contributed by general obesity, even among those with a normal BMI. To minimize the limitations of observational studies, I conducted Mendelian randomization (MR) analyses to investigate potential causal associations of breast cancer risk and body fat measures. GWAS were conducted to identify genetic variants associated with body fat percentage, whole body fat mass, trunk fat percentage and trunk fat mass to construct study instruments for MR analyses. I used summary statistics data from the Breast Cancer Association Consortium (98,842 cases and 83,464 controls) and individual-level data from the UKB (9,386 cases and 17,1648 controls) for the MR analysis. Consistent with previous studies, I found an inverse association between BMI/WHR and breast cancer risk. The novel findings from our study were that whole body fat mass and trunk fat mass were associated with an increased breast cancer risk after adjusting for BMI. I conducted additional analyses to explain the inverse association of BMI/WHR with breast cancer risk. I found that the polygenetic score for BMI was more strongly associated with measured BMI in younger than older age groups. My study provides strong evidence that high body fat mass is associated with elevated risk of breast cancer and other disease outcomes. Disease prevention programs should be designed to reduce visceral fat and body fat mass.