Molecular & Clinical Evaluation of Low HDL Syndromes

Atherosclerosis, Cardiovascular Diseases, Heart Diseases

To study the genetic cause of low HDL-C, a risk factor for premature atherosclerotic vascular disease in patients with normal total cholesterol. The focus is primarily on the identification of a single mutation, as has been demonstrated in one family.

BACKGROUND: Low levels of high density lipoprotein cholesterol (HDL-C) have been found to be associated with an increased risk for coronary artery disease (CAD). However, the genetic basis for this association is not well understood and the clinical implications of this association have not been extensively addressed. The study, in seeking to elucidate the genetic basis for low HDL-C and examine the clinical implications of low HDL-C, focuses upon an important research topic. DESIGN NARRATIVE: Specific aims of the study include: 1) Collection and characterization of plasma and DNA from probands with very low HDL-C. Linkage analysis will be performed using highly polymorphic markers within or near HDL-C candidate genes. The hypothesis to be tested is that polymorphic microsatellites segregate with the low HDL-C phenotype. 2\) Further genetic characterization of families evidence of linkage to specific HDL-C candidate genes identified in Specific Aim 1. The hypothesis to be tested is that structural variants in HDL-C candidates are responsible for low HDL-C. 3\) Evaluate the physiologic significance of novel genomic variants identified in Specific Aim 2. The hypothesis to be tested is that structural variants will affect expression of the gene product. 4\) Examine early atherosclerosis in low HDL-C syndromes. The hypothesis to be tested is that increased carotid intima-medial thickness is prevalent with isolated low HDL-C.

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