Coronary heart disease (CHD) is the leading cause of death in the Western societies. The overall aim in Project II is to identify genes for the most common familial dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL). FCHL is characterized by elevated levels of total cholesterol, triglycerides, or both. Many of the metabolic features of FCHL, e.g. hypertriglyceridemia and insulin resistance, also represent trait components of metabolic syndrome. We recently identified the first major gene, the upstream transcription factor 1 (USF1), for FCHL in FCHL families originating from the genetically isolated Finnish population.
Specific Aim 1 is concerned with investigating the USF1 variants for shared haplotypes and association using extended FCHL families from the more outbred Dutch population to clarify the significance of USF1 as an FCHL candidate in several populations.
In Specific Aim 2, we plan to identify the FCHL gene on 11 p underlying the linkage signals of Dutch and British families by genotyping the haplotype tag single nucleotide polymorphisms (htSNPs) in these FCHL families to define the linkage disequilibrium structure and common haplotypes of the linked region. We hypothesize that these common haplotypes capture most of the genetic variation, and the htSNPs forming them could be tested for association in the FCHL families. Simultaneous sequencing of a restricted number of relevant regional candidate genes is proposed as an alternative approach.
Specific Aim 3 is concerned with detecting gene expression changes characteristic of FCHL as a complementary way to traditional gene mapping. Expression differences between FCHL subjects and controls will be compared at the genomic level as well as based on their carrier status for the USF1 risk haplotype using Finnish and Dutch fat biopsies. We will also produce regional expression arrays for 11p to tackle candidate genes and their splice variants. Accomplishing these specific aims will provide a better understanding of the unknown genetic and molecular mechanisms of FCHL and CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL028481-21A1
Application #
7028142
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2005-07-01
Project End
2010-01-31
Budget Start
2005-07-01
Budget End
2006-01-31
Support Year
21
Fiscal Year
2005
Total Cost
$449,329
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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