The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation. 1. Introduction More than 2,200 Americans die from cardiovascular disease each day with 75% of those deaths attributable to atherosclerosis [1]. Atherosclerosis is characterized by the buildup of fatty lesions, inflammation, and scarring of arterial walls with oxidative stress as a primary contributing factor. Paraoxonase 1 (PON1) is a high-density-lipoprotein-(HDL-) associated esterase which appears to contribute to the antioxidant and antiatherosclerotic capabilities of HDL. PON1 is synthesized in the liver and secreted into the bloodstream where it is capable of breaking down both man-made and naturally occurring compounds. Named for its ability to hydrolyze organophosphates like paraoxon [2, 3] found in insecticides, PON1 is also able to hydrolyze N-acyl-homoserine, a lactone used by pathogenic bacteria [4], and lipid peroxides, thereby inhibiting the formation of foam cells known to contribute to atherosclerosis [5, 6]. PON1 has been widely studied following evidence that high activity levels decrease systemic oxidative stress and are associated with a lower incidence of cardiovascular events [7]. PON1 levels have been tied to a number of other disorders including type 1 and 2 diabetes [8, 9], thyroid dysfunction [10], uremia [11], renal failure [12], and inflammatory
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