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Journal of Lipid Research, Vol. 46, 1450-1456, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Determinants of variation in serum paraoxonase enzyme activity in baboons

David L. Rainwater^1,*, Michael C. Mahaney^*,, Xing Li Wang^*,, Jeffrey Rogers^*,, Laura A. Cox^* and John L. VandeBerg^*,

^* Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245
Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78245
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030

Published, JLR Papers in Press, April 16, 2005. DOI 10.1194/jlr.M400473-JLR200

¹ To whom correspondence should be addressed. e-mail: 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 PON 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 log of the odds (LOD) scores on the baboon homolog of human chromosome 7q21-22 (near PON1, the structural gene) of 9.1 on the low-cholesterol, high-fat diet and 4.1 on the high-cholesterol, high-fat diet (genome-wide P values were 1 x 10^–8 and 0.0018, respectively). Surprisingly, a second locus on the baboon homolog of human chromosome 12q13 gave a LOD score of 2.9 on the high-cholesterol, high-fat diet (genome-wide P value was 0.032). We identified several significant covariates, including age, sex, diet, and apolipoprotein A-I concentrations. We estimate that 53% of total trait variation in baboons is explained by genes and 17% by covariates, thus accounting for 70% of total variation in baboon PON.

Although the 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.

Supplementary key words PON1 • genetic • linkage analysis

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