An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia

Abstract

Objective Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. Methods and Results First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. Conclusion HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.

Common Genetic Variants Contribute to Primary Hypertriglyceridemia Without Differences Between Familial Combined Hyperlipidemia and Isolated Hypertriglyceridemia

“…A previous study in a population with a more severe hypertriglyceridemia than ours had shown that genetic variants in 7 loci and clinical variables explained ≈40% of triglyceride variation. 29,30 We found a similar percentage in our study.…”

“…In contrast with a previous study, 29,30 we have considered mild hypertriglyceridemia (triglyceride levels >200 mg/dL) to include isolated hypertriglyceridemia and FCHL. Johansen et al 29 studied 504 participants with triglycerides >500 mg/dL.…”

The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management

“…Familial should not be thought of as synonymous with monogenic; most cases of hypertriglyceridaemia are familial or inherited, but they are not monogenic. 35,36 …”

“…A genetic risk score, constructed by unweighted tallying of carrier status for triglyceride-raising alleles at the 32 triglyceride-associated loci, was on average higher for patients with hypertriglyceridaemia than for healthy controls (figure 2). 36,51 Thus, as for mutation-negative patients with familial hyper-cholesterolaemia and LDL-cholesterol raising variants, 41 an increased burden of triglyceride-raising alleles contributes to hypertriglyceridaemia susceptibility. 48,49 …”

ESC/EAS Guidelines for the management of dyslipidaemias

“…67,304 Moderate elevation of TG levels (between 2.0-10.0 mmol/L) is caused by the polygenic effect of multiple genes influencing both VLDL production and removal. In CVD prevention, polygenic moderate TG elevation is to be considered.…”