The metabolic syndrome is a common disorder posing a significant major risk for coronary heart disease and early mortality in the Western hemisphere. Central to its cardiovascular complications is the association of the syndrome with the specific abnormalities in plasma lipid and lipoprotein profiles including increased plasma triglycerides, decreased HDL cholesterol, and predominance of dense lipoprotein particles. In search for the genetic etiology of this lipid disorder, we identified a quantitative trait locus (QTL) on human chromosome 7q36 strongly linked to variation in plasma lipid levels. We hypothesize that this QTL contains genetic variants that contribute to alterations in biologic pathways underlying the genesis of the lipid disorder. To test for this hypothesis, we propose a comprehensive approach utilizing established resources and expertise to identify the functional sequence variants within this QTL. Specifically, we will 1.) identify single nucleotide polymorphisms (SNPs) and their haplotype and linkage disequilibrium structure across the entire QTL region; 2.) Analyze association of informative SNPs with plasma triglyceride levels, LDL levels, and lipoprotein density fractions using variance component linkage/disequilibrium analyses; and 3.) Identify potentially functional sequence variants in associated genes or genomic regions using Bayesian quantitative trait nucleotide analysis. This comprehensive application of newly available genomic technologies, novel statistical approaches, the DNA and phenotypic information available, and the consortium of expertise assembled behind this project will ensure the successful elucidation of the genetic etiology of this lipid disorder and consequently the development of effective means for prevention and/or treatment of cardiovascular complications of the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074168-03
Application #
6918676
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Jaquish, Cashell E
Project Start
2003-07-10
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$550,815
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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