Genetic factors influencing apolipoprotein AI and AII levels in a kindred with premature coronary heart disease

A single 51‐member kindred, ascertained on the basis of a normotriglyceridemic proband with depressed high‐density lipoprotein cholesterol (HDL‐C) and myocardial infarctions at ages 40 and 42, was studied with respect to quantitative variation in HDL‐C and apolipoprotein (apo) AI and AII levels. The results of bivariate segregation analysis suggest that the etiology of depressed HDL‐C involves one or possibly two major loci: one has a pleiotropic effect on apo AI and apo AII levels and, possibly another one that affects apo AI levels. Both the major loci were characterized as having a dominant allele leading to depression of the respective trait(s). In addition, analysis of the cosegregation of HDL‐C and apo AI levels gave evidence of residual nonfamilial factors common to both traits, leading to a positive covariance between them. This could reflect the role of apo AI in the transformation of nascent HDL‐C particles into mature ones via its cofactor activity to lecithin cholesterol acyltransferase. The proposed two‐locus model represents one possible etiology for the heterogeneous disorder of hypoal‐phalipoproteinemia. This analysis of a single pedigree does not completely define the genetic mechanism, but it does illustrate a useful new analytic approach.