Segregation analysis of HDL3-C levels in families of patients undergoing coronary arteriography at an early age.

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 HDL2 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 < or = 50 and women < or = 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.