J. Lipid Res.
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A more recent version of this article appeared on July 1, 2005

Papers In Press, published online ahead of print April 16, 2005
J. Lipid Res., doi:10.1194/jlr.M400473-JLR200
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Submitted on December 1, 2004
Revised on April 6, 2005
Accepted on April 6, 2005

Determinants of variation in serum paraoxonase enzyme activity in baboons

David L. Rainwater, Michael C. Mahaney, Xing Li Wang, Jeffrey Rogers, Laura A. Cox, and John L. VandeBerg

Genetics, Southwest Found Biomed Res, San Antonio, TX 78245-0549

Corresponding Author: david{at}darwin.sfbr.org

Paraoxonase (PON), an HDL-associated enzyme, is one of many circulating antioxidants thought to play a vital protective role. To better understand the determinants of quantitative variation in serum PON activity, we assayed paraoxonase in samples from 611 pedigreed baboons fed three diets. PON was measured enzymatically; the main determinant of variation was genetic and consisted of at least three components: two loci detected by linkage analyses and a residual polygenic component. Multipoint linkage analyses gave peak LOD scores on the baboon homologue of human chromosome 7q21-22 (near PON1, the structural gene) of 9.1 on low-cholesterol high-fat diet and of 4.1 on high-cholesterol high-fat diet (genome-wide P-values were 1 10-8 and 0.0018, respectively). Surprisingly, a second locus on the baboon homologue of human chromosome 12q13 gave a LOD score of 2.9 on high-cholesterol high-fat diet (genome-wide P-value was 0.032). We identified several significant covariates, including age, sex, diet, and apoAI concentrations. We estimate that 53% of total trait variation in baboons is explained by genes and 17% by covariates, thus accounting for approximately 70% of total variation in baboon paraoxonase. Although generation of free radicals is influenced primarily by environmental factors, our findings suggest strong genetic regulation of one component in the antioxidant defense system that plays a major role in susceptibility to atherosclerosis.


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