Genetics of Low Density Lipoprotein Subclasses in Hypercholesterolemia
Genetics of Low Density Lipoprotein Subclasses in Hypercholesterolemia
To perform genetic studies of low density lipoprotein (LDL) subclasses in 160 families in
 whom the probands had metabolically defined hypercholesterolemia.
BACKGROUND:

 Low density lipoprotein cholesterol has been convincingly established as a major coronary
 heart disease risk factor by many epidemiologic studies, clinical trials, and experimental
 studies. A strong inverse association exists between high density lipoprotein cholesterol and
 coronary heart disease. However, the status of very low density lipoprotein (VLDL)
 cholesterol and plasma triglyceride levels as independent risk factors for cardiovascular
 disease is less clear. Case control studies have shown a positive association between
 coronary heart disease and plasma levels of apoprotein B, the major protein on LDL particles,
 and an inverse relationship with apoprotein AI, the primary protein constituent of HDL
 particles. In fact, it has been proposed that plasma levels of the apoproteins may be
 stronger risk factors than lipid levels. Thus, understanding the mechanisms underlying
 variations in both lipoprotein and apoprotein levels among individuals is essential to
 elucidating the etiology of coronary heart disease in the general population.

 Cardiovascular disease is also known to cluster in families, and this may be related to the
 clustering of lipid and lipoprotein levels among family members. A review suggested that the
 familial aggregation of heart disease may be primarily a reflection of the familial
 aggregation of known risk factors, including cholesterol levels. The work of Goldstein and
 Brown on familial hypercholesterolemia demonstrated that genetic control of lipoprotein
 metabolism can play a causative role in the development of atherosclerosis. However, familial
 hypercholesterolemia is a relatively rare disorder: the prevalence of heterozygotes is
 estimated to be 1 in 500, homozygotes 1 in a million. In 1987, little was understood about
 more common genetic contributions to lipid and lipoprotein abnormalities leading to the
 familial aggregation of coronary heart disease.

 DESIGN NARRATIVE:

 The design was that of a cross-sectional family study. The recruitment and screening of
 probands were conducted over a four-year period at the University of Texas at Dallas under
 separate funding. The recruitment and screening of first-degree relatives were carried out at
 Berkeley. Blood samples were obtained from relatives for LDL subclass analysis and for lipid
 and apoprotein determination. An interview was conducted to obtain demographic information
 and information on behavioral and environmental risk factors such as smoking, exercise, and
 diet. The data were used to determine whether LDL subclasses were genetically controlled in
 families with hypercholesterolemia due to overproduction of LDL or defective clearance of LDL
 particles. Segregation analysis of LDL subclasses in these two types of families was
 performed to search for a single major genetic locus and to simultaneously test for the
 influence of polygenes and environmental effects. The relationships between the LDL subclass
 phenotype characterized by a predominance of small, dense LDL and overproduction of
 apoprotein B and LDL clearance defects were investigated in family members. A determination
 was made as to whether an age-of-onset effect existed for the expression of LDL subclass
 phenotypes. Genetic-environmental interactions were also studied.
No eligibility criteria