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

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

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(8): 1916-U460.

DOI：10.1161/ATVBAHA.111.226365

• lipoproteins
• genetic risk scores
• genetic variation
• hypertriglyceridemia
• pleiotropy

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.)

• 出版日期2011-8