Document Detail


An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.
MedLine Citation:
PMID:  21597005     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
CONCLUSIONS: HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
Authors:
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 Elosua; 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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-05-19
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  31     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-21     Completed Date:  2011-09-20     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1916-26     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, Canada.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Alleles
Apolipoprotein E2 / genetics
Case-Control Studies
Cholesterol, HDL / blood,  genetics
Cholesterol, LDL / blood,  genetics
Female
Genetic Predisposition to Disease
Genetic Variation
Humans
Hyperlipoproteinemia Type IV / blood,  genetics
Hypertriglyceridemia / blood*,  genetics*
Lipids / blood*,  genetics*
Male
Middle Aged
Multifactorial Inheritance
Phenotype
Risk Factors
Triglycerides / blood,  genetics
Grant Support
ID/Acronym/Agency:
CTP-79853//Canadian Institutes of Health Research; MOP-13430//Canadian Institutes of Health Research; MOP-79523//Canadian Institutes of Health Research; Z99 HL999999/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apolipoprotein E2; 0/Cholesterol, HDL; 0/Cholesterol, LDL; 0/Lipids; 0/Triglycerides
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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