A major gene influences variation in large HDL particles and their response to diet in baboons.

Some baboons accumulate appreciable amounts of large apoE-rich HDLs (HDL(1)) which are similar to those reported in humans with several different dyslipoproteinemias. We estimated HDL(1) cholesterol concentrations by gradient gel electrophoresis of serum samples obtained from 634 pedigreed baboons fed with three diets differing in levels of fat and cholesterol. The HDL(1) trait was highly heritable on each diet (0.390< or =h(2)< or =0.528). Segregation analyses yielded significant evidence that a single major gene plus polygenes affected HDL(1) on a high-fat low-cholesterol diet. The major gene explained approximately 56% of total trait variance and 90% of the additive genetic variance in HDL(1) levels in these baboons. Bivariate one-locus segregation analyses indicated that this major gene exerts significant pleiotropic effects on a number of traditional HDL traits on all three diets, including HDL size distributions, and concentrations of HDL-C, apoAI, and apoE. Linkage analyses showed that this major gene was not located in chromosomal regions that contain six candidate genes whose protein products are important to HDL metabolism (LCAT, CETP, APOA1, APOE, ABCA1, LIPC). Our results suggest this major gene in baboons plays a pivotal role in HDL metabolism, but is unlikely to code for any of the proteins previously implicated in studies of human HDL(1).