Two Major Loci Control Variation in β-Lipoprotein Cholesterol and Response to Dietary Fat and Cholesterol in Baboons

Abstract —We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in β-lipoproteins (low density lipoprotein cholesterol [LDLC]) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high–saturated fat (lard) diet, and a high-cholesterol, high–saturated fat diet. In addition to baseline levels (LDLCBase), we analyzed two variables for diet response: LDLCRF, which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLCRC, which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities ( h 2) of the 3 traits were 0.59 for LDLCBase, 0.14 for LDLCRF, and 0.59 for LDLCRC. In addition, LDLCBase and LDLCRC had a significant genetic correlation (ie, ρG=0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLCRC and some genetic variation in LDLCBase and LDLCRF and confirmed the presence of a different major locus that influences LDLCBase alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations.