Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients

The serum enzyme paraoxonase (PON) protects LDLs from oxidative stress. We recently identified promoter polymorphisms of the PON gene that strongly af fect gene expression and serum levels of the enzyme. The present study test ed the hypothesis that promoter polymorphism T(-107)C could be a risk facto r for vascular disease in type 2 diabetic patients by virtue of its ability to modulate serum concentrations of the antioxidant enzyme. The low-expres sor genotype (TT) was associated with significantly lower serum PON concent rations, and it was over-represented in type 2 diabetic patients with coron ary heart disease (CHD) (TT vs. TC+CC: odds ratio [OR] 1.64 [95% CI 1.03-2. 61], P < 0.05). The association of the low-expressor genotype with an incre ased risk of disease was independent of other risk factors, including the c oding region Q191R polymorphism (OR 2.12 [95% CI 1.19-3.70], P = 0.01). How ever, an interaction of the promoter polymorphism with the Q191R polymorphi sm, which was previously identified as an independent risk factor, was obse rved. The low-expressor promoter allele (-107T) associated with the high-ri sk 191R allele showed a lower-than-expected level of risk (OR 2.21 vs. the expected 4.76). The data are consistent with the hypothesis that low expres sion of the antioxidant enzyme PON increases the risk of CHD. Moreover, the promoter polymorphism appears to have a modulating effect on risk that is associated with the coding region polymorphism Q191R, This study indicates a strong genetic component to the antioxidant capacity of HDLs.