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

Abstract

E levated circulating levels of total cholesterol (TC), lowdensity lipoprotein (LDL)-cholesterol (LDL-C), and triglycerides, as well as decreased levels of high-density lipoprotein-cholesterol (HDL-C) are associated with increased risk of cardiovascular disease.1,2 Dyslipidemia is a heterogeneous complex state, which increases risk of atherosclerotic cardiovascular disorders and a state for which both genetic predisposition and lifestyle factors contribute to the phenotype and its progression. The estimated heritability of lipid traits is 40% to 60% 3,4 and genome-wide association studies have to date identified 157 genomic loci that are robustly associated with circulating fasting lipid concentrations. 5,6 However, these loci explain only ≈12% to 14% of the genetic variance of each lipid trait. 5,6 Also, a recently published whole-genome sequencing study encompassing 962 individuals suggested that common single nucleotide polymorphisms (SNPs) may account for 61.8% of the variance in HDL-C levels and that many SNPs with small effect size contribute to the genetic architecture of lipid levels. 7 Thus, it may be reasonable to combine the SNPs in a cumulative genetic risk score (GRS) to study the effects of having multiple common genetic SNPs. A GRS based on 32 triglycerides loci was found to modestly 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 whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. Methods and Results-The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, highdensity lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from P=3.3×10 -69 to P=1.1×10 -123 ). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (P interaction =9.8×10 -5 and 2.0×10 -5 , respectively, ...

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

“…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.…”

“…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).…”

Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?

“…[11][12][13] Interactions between genetic variants and obesogenic lifestyle factors (primarily diet and physical activity) in relation to blood triglyceride concentrations have been explored extensively. 14,15 Data recently published from 2 Danish cohorts suggest that previously established triglyceride-associated loci modify the association of body mass index (BMI) and triglycerides, 16 but to our knowledge, no independent replication studies have been published.…”

Frequencies of Genetic Polymorphisms of the Cholesterol and Statin Metabolic Pathway Genes among Healthy South Indian Tamil Population

“…Till now, 157 gene loci have been studied for association with blood lipid levels which could explain only 12-14% variation in the lipid levels. 4 The clinical significance of genetic variants associated with lipid abnormalities depends on the frequency of genetic variants in the population of interest. Further, the normative data of frequency of single nucleotide polymorphism (SNP) is essential for planning and conducting genotypephenotype association studies.…”