Abstract

Although of great clinical and biological importance, the role of genotype-diet interaction in lipoprotein metabolism and atherosclerosis is still poorly understood. We analyzed serum apolipoprotein A-I (apo A-I) concentrations of approximately 600 pedigreed baboons that were fed two dietary regimens: (1) a basal diet and (2) an atherogenic (high-cholesterol, saturated-fat) diet. Complex segregation analysis was performed separately for apo A-I concentrations in each dietary environment. A major locus model with a recessive allele for high levels of apo A-I and a polygenic component best fit the family data for both diets. Using bivariate segregation analysis, we showed that the major genes detected in the univariate analyses represent two distinct loci that act additively to determine apo A-I concentrations. These two loci accounted for approximately 40% of the total phenotypic variance in apo A-I levels in each dietary environment and were also responsible for 33% of the variation in apo A-I response to the atherogenic diet. Both major loci were influenced by genotype-diet interaction in which the two-locus genotypes exhibited heterogeneous responses to the atherogenic diet. Most genotypes responded to the atherogenic diet with an increase in apo A-I, but two genotypes showed a decrease that can be traced to the effect of one of the major loci. The presence of two major loci and genotype-diet interaction may be responsible for the equivocal results obtained in human pedigree studies of apo A-I.