Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 31, Issue 8, Pages 1916-U460Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.111.226365
Keywords
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-13430, MOP-79523, CTP-79853]
- University of Western Ontario
- Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario
- Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I)
- Martha G. Blackburn Chair in Cardiovascular Research
- Heart and Stroke Foundation of Ontario [NA-6059, T-6018, PRG-4854]
- Pfizer
- Genome Canada through the Ontario Genomics Institute
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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. (Arterioscler Thromb Vasc Biol. 2011; 31: 1916-1926.)
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