Paraoxonase1-192 polymorphism modulates the nonfatal myocardial infarction risk associated with decreased HDLs.
Serum paraoxonase1 (PON1), a high density lipoprotein (HDL)-linked enzyme, appears to have a role in the protection of low density lipoproteins from oxidative stress. PON1 enzyme activity for paraoxon as a substrate is modulated, along with others at the PON1 locus, by the PON1-192 polymorphism, which contains low paraoxon-activity and high paraoxon-activity alleles (Q and R, respectively). The association of PON1 with HDL suggests that impaired serum concentrations of the lipoprotein could have consequences for the susceptibility to oxidative stress. Because PON1-192 polymorphism strongly influences PON1 activity toward paraoxon, we tested the hypothesis that this polymorphism may modulate the myocardial infarction (MI) risk associated with low HDL cholesterol concentrations. Two hundred eighty consecutive MI patients and 396 control subjects were studied. When considered as a whole, PON1-192 genetic polymorphism was not associated with higher MI risk. In the entire population, decreased HDL cholesterol concentration (<0.90 mmol/L in men and <1.11 mmol/L in women) conferred an MI risk of 2.56 (P=0.0001) compared with normal HDL levels. The risk increased to 4.51 (P<0.0001) in QQ homozygous HDL-deficient subjects relative to QQ homozygotes with normal HDL levels, decreased to 1.83 (P=0.1046) in QR heterozygote HDL-deficient subjects, and also decreased (to 1.41, P=0.6243) in RR homozygote HDL-deficient individuals compared with RR carriers with normal HDL cholesterol concentration. The effect of PON1-192 genotypes on the association of low HDL cholesterol levels and MI was related to gene dosage. A significantly decreased enzyme activity was found in HDL-deficient MI patients compared with HDL-deficient control subjects (median 208 U/L [interquartile range 136 to 298 U/L] versus median 235 U/L [interquartile range 163 to 350 U/L], respectively; P=0.025]. QQ homozygous MI patients showed the greatest difference of PON1 activity levels between normal and HDL-deficiency state groups (14.9%, P=0.002). Our observations raise the question of whether the decrease in PON1 activity and the MI risk associated with HDL deficiency are more evident in the low paraoxon-activity QQ genotype. It can be argued that the low paraoxon-activity QQ genotype, which may be adequate to prevent lipid peroxidation in normolipidemic subjects, may be insufficient when an HDL-deficiency state and low PON1 activity reflecting oxidative stress coexist. The risk of nonfatal MI is increased in HDL-deficiency states, principally among subjects carrying the low paraoxon-activity QQ genotype.