M ore than 600 million people are estimated to be obese worldwide, 1 which is thought to be primarily a consequence of lifestyles characterized by consumption of energy-dense foods with poor nutritional content and lack of physical activity in the workplace and at home. The high prevalence of obesity is of considerable concern owing to the plethora of its life-threatening sequelae, including type 2 diabetes mellitus, coronary heart disease, and cerebrovascular disease.2 Accumulation of triglycerides in adipose, muscle, liver, and blood cells can impair cellular insulin action and glucose uptake and promote the accumulation of atherosclerotic arterial plaques.3,4 Therefore, elevated triglycerides and triglyceride-rich lipoproteins are important intermediate risk factors for type 2 diabetes mellitus and are causal Background-Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability. was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (P interaction =0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS TG ×BMI interaction effect (P interaction =6.0×10 -4 ), which was strengthened by including data from the Danish cohorts (P interaction =6.5×10 -7 ). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS TG ×BMI×sex) was observed (P interaction =0.03), where the WGRS TG ×BMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci. Conclusions-Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females. (Circ Cardiovasc Genet. 2016;9:162-171.