Refinement of a published gene-physical activity interaction impacting HDL-cholesterol: role of sex and lipoprotein subfractions.

Large-scale gene-environment interaction (GxE) discovery efforts often involve compromises in the definition of outcomes and choice of covariates for the sake of data harmonization and statistical power. Consequently, refinement of exposures, covariates, outcomes, and population subsets may be helpful to establish often-elusive replication and evaluate potential clinical utility. Here, we used additional datasets, an expanded set of statistical models, and interrogation of lipoprotein metabolism via nuclear magnetic resonance (NMR)-based lipoprotein subfractions to refine a previously discovered GxE modifying the relationship between physical activity (PA) and HDL-cholesterol (HDL-C). This GxE was originally identified by Kilpeläinen et al., with the strongest cohort-specific signal coming from the Women's Genome Health Study (WGHS). We thus explored this GxE further in the WGHS (N = 23,294), with follow-up in the UK Biobank (UKB; N = 281,380), and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 4,587). Self-reported PA (MET-hrs/wk), genotypes at rs295849 (nearest gene: