Human Lipoprotein Pathophysiology - Subproject: Genetics of Familial Combined Hyperlipidemia

Atherosclerosis, Cardiovascular Diseases, Heart Diseases, Hypercholesterolemia, Hyperlipidemia, Familial Combined

To conduct focused studies of lipoprotein physiology and pathophysiology in genetically characterized patients with the objectives of understanding disease mechanisms, developing better treatments, and identifying and preventing early vascular disease.

BACKGROUND: Premature vascular disease in young hyperlipidemic subjects remains a major unsolved health problem in terms of pathogenesis and treatment. Research advances have led to new markers for genetic analysis, new methods for studying lipoprotein metabolism and atherosclerotic disease progression and regression, and reference values for diagnosing hyperlipidemia. DESIGN NARRATIVE: Attention is focused on the molecular, genetic and pathophysiological basis of the inherited dyslipoproteinemias associated with premature coronary artery disease with particular reference to familial combined hyperlipidemia, familial moderate hypercholesterolemia, familial elevation of Lp(a) and the carrier state for homocysteinemia. Coordinated studies of characterization of the pathophysiological state, the identification of possible molecular biological defects and the evaluation of these results in families by statistical genetic techniques are performed in each disorder. The role of protein mediated intravascular modification of lipoproteins and the role of oxidation of lipoproteins in each disorder will lead to characterization of these genetic lipoprotein abnormalities. The study is a subproject within a program project grant. The subproject on the genetics of familial combined hyperlipidemia (FCHL) was renewed in 1999 through 2010 to continue mapping the apoB elevating gene l(BEL) level using a genomic search in pedigrees with familial combined hyperlipidemia. The major focus of the genetic analyses are the 15 FCHL families under the BEL segregation analysis model in a power analysis. These families also show the most evidence for segregation at an apoB elevating gene locus. Genotyping for a 10 centimorgan genomic scan has been completed for these families.

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