Paraoxonase was identified as a genetic risk factor for
cardiovascular disease (CVD) in recent studies focusing on a polymorphism affecting position 191. A second polymorphism of the
paraoxonase gene affects position 54 and involves a
methionine (M allele) to
leucine (L allele) change. It was investigated in diabetic patients (n = 408) with and without
vascular disease. There were highly significant differences in plasma concentrations and activities of
paraoxonase between genotypes defined by the 54 polymorphism: MMAA, MLAA, LLAA;
protein, 65.3+/-18.0, 77.9+/-18.0, 93.5+/-26.0 microg/ml; P < 0.0001: activity (
phenylacetate), 48.6+/-13.5, 64.1+/-14.5, 68.1+/-13.0 U/ml; P < 0.0001. The 191 variant had little impact on
paraoxonase concentrations. Homozygosity for the L allele was an independent risk factor for CVD (odds ratio 1.98 (1.07-3.83); P = 0.031). A linkage disequilibrium (P < 0.0001) was apparent between the mutations giving rise to
leucine and
arginine at positions 54 and 191, respectively. The study underlines that susceptibility to CVD correlates with high activity
paraoxonase alleles. The 54 polymorphism would appear to be of central importance to
paraoxonase function by virtue of its association with modulated concentrations. The latter could explain the association between both the 54 and 191 polymorphisms and CVD.