Do genetic factors modify the relationship between obesity and hypertriglyceridemia

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. Methods and Results - We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmo Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS TG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS TG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m 2) associated with 2.8% (P=8.4×10 -84) higher triglyceride concentration and each additional WGRS TG unit with 2% (P=7.6×10 -48) higher triglyceride concentration. Each unit of the WGRS TG 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.