A Common Genetic Mechanism Determines Plasma Apolipoprotein B Levels and Dense LDL Subfraction Distribution in Familial Combined Hyperlipidemia

Suh-Hang Hank Juo1,2, Sebastian J. H. Bredie3, Lambertus A. Kiemeney4, Pierre N. M. Demacker3, and Anton F. H. Stalenhoef3

1National Human Genome Research Institute, National Institutes of Health, Baltimore;
2Laboratory of Statistical Genetics, Rockefeller University, New York; and
3Department of Medicine, Division of General Internal Medicine, and
4Department of Epidemiology and Urology, University of Nijmegen, Nijmegen

American Journal of Human Genetics , 63, 586-594 (1998)

Abstract

Familial combined hyperlipidemia (FCH) is a common lipid disorder characterized by elevations of plasma cholesterol and/or triglyceride in first-degree relatives. A predominance of small, dense LDL particles and elevated apolipoprotein B (apoB) levels is commonly found in members of FCH families. Many studies have investigated the genetic mechanisms determining individuals' lipid levels, in FCH families. Previously, we demonstrated a major gene effect on LDL particle size and codominant Mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined FCH families. An elevation of apoB levels is associated metabolically with a predominance of small, dense LDL particles in FCH. To establish whether a common gene regulates both traits, we conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. In this study, we found that 66% of the total phenotypic correlation is due to shared genetic components. Further bivariate segregation analysis suggested that both traits share a common major gene plus individual polygenic components. This common major gene explains 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. Our study suggests that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCH in the families we studied.