DNA POLYMORPHISMS IN 2 PARAOXONASE GENES (PON1 AND PON2) ARE ASSOCIATED WITH THE RISK OF CORONARY HEART-DISEASE

A common polymorphism at codon 192 in the human paraoxonase (PON) 1 ge ne has been shown to be associated with increased risk for coronary he art disease (CHD) in Caucasian populations. However, these findings ha ve not been reported consistently in all Caucasian and non-Caucasian p opulations, suggesting that this is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Re cently, two other PON-like genes, designated ''PON2'' and ''PON3,'' ha ve been identified, and they are linked with the known PON1 gene on ch romosome 7. Identification of additional polymorphisms in the PON-gene cluster may help to locate the functional polymorphism. In this repor t, we describe the existence of a common polymorphism at codon 311 (Cy s-->Ser; PON2S) in the PON2 gene, as well as its association with CHD alone and in combination with the PON1 codon 192 polymorphism in Asia n Indians. The frequency of the PON2S allele was significantly higher in cases than in controls (.71 vs. .61; P = .016). The age-and sex-ad justed odds ratio (OR) was 2.5 (95% confidence interval [95% CI] = 1.8 -3.1; P = .0090) for the PON2S allele carriers. Further stratificatio n of the PON2S association, on the basis of the presence or absence o f the PON1B allele, showed that the CHD risk associated with the PON2 S allele was confined to PON1*B-allele carriers. Likewise, the PON1*B -allele risk was present only among PON2S carriers. Age-and sex-adjus ted ORs for the PON2S and PON1*B were 3.6 (95% CI = 2.6-4.6; P = .011 ) and 2.9 (95% CI = 2.4-3.5; P = .0002) among the PON1B and PON2*S ca rriers, respectively. Our data indicate that both polymorphisms synerg istically contribute to the CHD risk in this sample and that this gene tic risk is independent of the conventional plasma lipid profile.