Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?

Abstract

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.

Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years

“…It would be of interest to follow-up on this suggestive finding in a larger cohort and preferentially with objectively measured physical activity. Also of notice, it has recently been suggested that the interaction between the triglyceride wGRS and BMI is stronger in women (17). In the present study, we confirm this observation also for the interaction between the wGRS and HOMA-IR.…”

“…Previous studies of interactions in cross-sectional settings have found comparable interactions suggesting a stronger association between the wGRS and triglycerides in obese or in more insulin-resistant individuals (14)(15)(16)(17)19). In this study, we demonstrate that the interaction with HOMA-IR is also evident in a prospective setting consolidating the results from previous studies using cross-sectional data.…”

“…We and others have reported interactions with triglyceride GRS in the cross-sectional setting, including interactions with BMI and insulin resistance using homeostatic model assessment of insulin resistance (HOMA-IR) (14)(15)(16)(17)19). Taken together these cross-sectional results point toward a bigger effect of the triglyceride GRS on triglycerides in obese individuals compared with lean individuals.…”

“…However, because obesity and insulin resistance often coincide and are associated with lifestyle-related parameters, it is uncertain which of these factors is more relevant for the interactions observed. Moreover, a recent study has suggested that the interaction between triglyceride GRS and BMI is stronger in women (17).…”

“…While many studies have consolidated the effect of genetic risk variants in cross-sectional studies, fewer studies have focused on prospective analyses (11)(12)(13) and interactions with metabolic and lifestyle factors (14)(15)(16)(17). A few studies based on genetic risk scores (GRSs) with 32 and 40 triglyceride-associated SNPs, respectively, have found that a higher genetic load associates with increased concentration of triglycerides over 9 and 10 years of follow-up (12,13).…”