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Keywords:

  • coronary artery disease;
  • epistasis;
  • gene–environment interaction;
  • paraoxonase;
  • smoking

Polymorphisms of paraoxonase gene (PON) cluster have been investigated in numerous studies for their association with myocardial infarction (MI) but the results have been conflicting. Epistasis and gene–environment interactions at this locus could possibly modulate susceptibility toward MI and account for the discrepancies. We carried out a case–control study (211 MI patients and 370 control subjects) to test association of PON cluster polymorphisms with MI, their interactions with each other and with smoking. Genotyping was performed by PCR–restriction fragment length polymorphism based assays. The Q192R, C-108T, and A148G polymorphisms were associated with MI. Two haplotypes consisting of C-108T, C311S, and A148G, having allele frequencies of 0.17 and 0.14 in the control population, predisposed to MI (global haplotype statistic χ2 = 34.74, df = 15, p = 0.0027). Multifactor dimensionality reduction analysis showed a significant three-locus model (p = 0.02) involving these three polymorphisms, suggesting a potential gene–gene interaction between PON1 and PON2. These polymorphisms also interacted with smoking, in a three-locus and a four-locus model (p = 0.01 and p = 0.05, respectively). Additionally, the R192 allele may advance the age-at-onset of MI. The PON cluster appears to be a susceptibility locus for MI in Pakistani population, and the susceptibility is modulated through gene–gene and gene–environment interactions.