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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2696.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

David L. Rainwater; Candace M. Kammerer; John L. VandeBerg

From the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex.

Correspondence to David L. Rainwater, PhD, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail david{at}darwin.sfbr.org

Abstract—We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fat 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 cholesterol. Measurement of serum concentrations in samples taken while the baboons 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%, respectively, when dietary fat and cholesterol were increased (P<0.001). As expected, most of the variation in Lp(a)_Basal was influenced by genes (h²=0.881). However, less than half of the variation in Lp(a)_RC was influenced by genes (h²=0.347, P<0.0001), whereas the increase due to dietary fat alone was not significantly heritable (h²=0.043, P=0.28). To determine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkage analyses by using LPA genotypes inferred from the apo(a) isoform phenotypes. 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 density lipoprotein cholesterol [LDLC; ie, non–high density lipoprotein cholesterol less the cholesterol contribution from Lp(a)]. LDLC_Basal was weakly correlated with Lp(a)_Basal (_P=0.018). However, LDLC_RC and Lp(a)_RC were strongly correlated (_P=0.382), and partitioning the correlations revealed significant genetic and environmental correlations (_G=0.587 and _E=0.251, respectively). The results suggest that increasing both 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 LDLC levels as well. The gene(s) influencing Lp(a) response to dietary cholesterol is not linked to the LPA locus.

Key Words: Lp(a) • apo(a) • baboons • genetics