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

2011; Lippincott Williams & Wilkins; Volume: 31; Issue: 8 Linguagem: Inglês

10.1161/atvbaha.111.226365

1524-4636

Christopher T. Johansen, Jian Wang, Matthew B. Lanktree, Adam D. McIntyre, Matthew R. Ban, Rebecca A. Martins, Brooke A. Kennedy, Reina G. Hassell, Maartje E. Visser, Stephen M. Schwartz, Benjamin F. Voight, Roberto Elosúa, Veikko Salomaa, Christopher J. O’Donnell, Geesje M. Dallinga‐Thie, Sonia S. Anand, Salim Yusuf, Murray W. Huff, Sekar Kathiresan, Henian Cao, Robert A. Hegele,

Cancer, Lipids, and Metabolism

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.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.HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.