Evidence that multiple genes influence baseline concentrations and diet response of Lp(a) in baboons

We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fa t and cholesterol in 633 baboons fed a series of 3 diets: a basal diet low in cholesterol and fat, a high-fat diet, and a diet high in fat and cholest erol. Measurement of serum concentrations in samples taken while the baboon s were sequentially fed the 3 diets allowed us to analyze 3 Lp(a) variables : Lp(a)(Basal), Lp(a)(RF) (response to increased dietary fat), and Lp(a)(RC ) (response to increased dietary cholesterol in the high-fat environment). On average, Lp(a) concentrations significantly increased 6% and 28%, respec tively, when dietary fat and cholesterol were increased (P < 0.001). As exp ected, most of the variation in Lp(a)(Basal) was influenced by genes (h(2) = 0.881). However, less than half of the variation in Lp(a)(RC) was influen ced by genes (h(2) = 0.347, P < 0.0001), whereas the increase due to dietar y fat alone was not significantly heritable (h(2) = 0.043, P = 0.28). To de termine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkag e analyses by using LPA genotypes inferred from the apo(a) isoform phenotyp es. All of the genetic variance in Lp(a)(Basal) concentration was linked to the LPA locus (log of the odds [LOD] score was 30.5). In contrast, linkage analyses revealed that genetic variance in Lp(a)(RC) was not linked to the LPA locus (LOD score was 0.036, P > 0.5). To begin identifying the non-LPA genes that influence the Lp(a) response to dietary cholesterol, we tested, in bivariate quantitative genetic analyses, for correlation with low densi ty lipoprotein cholesterol [LDLC; ie, non-high density lipoprotein choleste rol less the cholesterol contribution from Lp(a)]. LDLCBasal was weakly cor related with Lp(a)(Basal) (rho(P) = 0.018). However, LDLCRC and Lp(a)(RC) w ere strongly correlated (rho(P) = 0.382), and partitioning the correlations revealed significant genetic and environmental correlations (rho(G) = 0.58 7 and rho(E) = 0.251, respectively). The results suggest that increasing bo th dietary fat and dietary cholesterol caused significant increases in Lp(a ) concentrations and that the response to dietary cholesterol was mediated by a gene or suite of genes that appears to exert pleiotropic effects on LD LC levels as well. The gene(s) influencing Lp(a) response to dietary choles terol is not linked to the LPA locus.