SEGREGATION ANALYSIS OF 2-LOCUS MODELS REGULATING APOLIPOPROTEIN-A1 LEVELS

For quantitative traits associated with risk to complex diseases, such as heart disease, single major locus models are likely to be too simp listic. Currently, researchers have begun to use oligogenic models of inheritance, but the resolving power of these models remains to be det ermined. As the major apoprotein of high density lipoprotein (HDL), ap olipoprotein A1 (apo-A1) is generally accepted as a protective factor for coronary artery disease. Although familial aggregation of apo-A1 l evels has been reported, the mode of inheritance of apo-A1 remains ill defined. In the present study, we conducted a segregation analysis co mparing a series of one-locus and two-locus univariate models for apo- A1 levels in a sample of 137 families ascertained through probands und ergoing elective, diagnostic coronary angiography. A two-locus Mendeli an model fit these data significantly better than any one-locus model. The incorporation of the second major locus into the model of inherit ance leads to a significant improvement in the fit, and a significant decrease of the residual heritability. The best-fitting model included two loci with a reciprocal pattern of epistasis generating 4 distinct genotypic distributions. Taken together, these two major loci account for 58% of the variance of adjusted apo-A1 levels. This demonstration of a second major locus controlling apo-A1 levels may explain the equ ivocal results obtained from previous studies. This two-locus model ma y be more powerful for linkage analysis to map one or both of these qu antitative trait loci. (C) 1998 Wiley-Liss, Inc.