Interactions of Lipid Genetic Risk Scores with Estimates of Metabolic Health in a Danish Population

BACKGROUND: -There are several well-established lifestyle factors influencing dyslipidemia and currently, 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested if genetic risk scores (GRS) of lipid-associated SNPs associate with fasting serum lipid traits and if the effects are modulated by lifestyle factors or estimates of metabolic health.

METHODS AND RESULTS: -The SNPs were genotyped in two Danish cohorts: Inter99 (n=5,961) for discovery analyses and Health2006 (n=2,565) for replication. Based on published effect sizes of SNPs associated with circulating fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol or triglyceride, four weighted GRS (wGRS) were constructed. In a cross-sectional design, we investigated if the effect of these wGRSs on lipid levels were modulated by diet, alcohol consumption, physical activity and smoking or the individual metabolic health status as estimated from BMI, waist circumference and insulin resistance assessed using HOMA-IR. All four lipid wGRSs associated strongly with their respective trait (from P=3.3×10(-69) to P=1.1×10(-123)). We found interactions between the triglyceride wGRS and BMI and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (Pinteraction=9.8×10(-5) and 2.0×10(-5), respectively in combined analysis).

CONCLUSIONS: -Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride SNPs. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.