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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1307-1313.)
© 1995 American Heart Association, Inc.

Articles

Segregation Analysis of HDL₃-C Levels in Families of Patients Undergoing Coronary Arteriography at an Early Age

J. Coresh; T.H. Beaty; V.L. Prenger; J. Xu; P.O. Kwiterovich, Jr

From the Department of Epidemiology (J.C., T.H.B., J.X.), The Johns Hopkins School of Hygiene and Public Health, and the Departments of Medicine (J.C.) and Pediatrics (P.O.K.), The Johns Hopkins School of Medicine, and the Division of Human Genetics (V.L.P.), University of Maryland, Baltimore, Md.

Correspondence to Josef Coresh, MD, PhD, Welch Center for Prevention, Epidemiology and Clinical Research, 2024 E Monument, Baltimore, MD 21205-2223. E-mail coresh@welchlink.welch.jhu.edu.

Abstract HDL cholesterol (HDL-C) level is a risk factor for coronary heart disease. Studies have shown a strong genetic influence on HDL-C levels in addition to environmental influences, but no definite major gene control has been demonstrated. Since HDL subfractions may better reflect the actions of distinct metabolic alterations than total HDL, we tested the hypothesis that the amount of cholesterol in the denser HDL₃ subfraction (HDL₃-C) is under the control of a major gene. The study population included 676 family members of 116 probands who underwent coronary arteriography at an early age (men 50 and women 60 years). HDL₃-C level was measured by using enzymatic methods after preparative ultracentrifugation at a density of 1.125 g/mL. HDL₃-C was adjusted for age, gender, alcohol consumption, and smoking, which combined accounted for 3% of its variance. Segregation analysis was conducted on adjusted HDL₃-C by using regressive models. The familial correlations for HDL₃-C levels were spouse .03±.08, parent-offspring .14±.05, and sibling .24±.05. The data strongly supported a codominant mendelian model, with the common allele coding for lower HDL₃-C levels and the rarer allele (frequency, 25%) coding for higher HDL₃-C levels. This major gene explained 34% of the variation in HDL₃-C levels and 9% of the variation in total HDL-C levels. These results suggest that HDL₃-C levels exhibit clearer genetic control than total HDL-C and may therefore be a useful target for further genetic studies.

Key Words: HDL₃ • HDL • segregation analysis • major gene • population genetics

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