The 242T variant of the CYBA gene polymorphism increases the risk of coronary artery disease associated with cigarette smoking and hypercholesterolemia.

OBJECTIVES

Hypercholesterolemia and cigarette smoking increase superoxide anion production, which is involved in many proatherosclerotic processes. NAD(P)H oxidases are the main source of superoxides in the vasculature, and the phagocyte oxidase (p22phox) encoded by the CYBA gene is a critical component of NAD(P)H oxidases. The 242T CYBA allele is associated with an increased low-density lipoprotein oxidation and superoxide production. This report focuses on the interactions between C242T CYBA polymorphism and traditional risk factors of coronary artery disease (CAD), such as cigarette smoking and hypercholesterolemia.

METHODS

We have studied 341 individuals, including 172 patients with angiographically confirmed CAD and 169 blood donors with no known history of cardiovascular disease. The C242T CYBA polymorphism was genotyped using the PCR-restriction fragment-length polymorphism method. To determine the possible interactions between CYBA genotypes and the traditional risk factors for CAD, we used multivariate logistic regression analysis (cumulative effects) and the 4 x 2 table approach (synergistic/antagonistic effects).

RESULTS

We have found a strong cumulative effect of the 242T allele carrier state and cigarette smoking and hypercholesterolemia. The risk of CAD associated with the presence of cigarette smoking and hypercholesterolemia was stronger in 242T carriers (odds ratio=17.88, P<0.00000) than in CC homozygotes (odds ratio=3.75, P<0.00000). Estimated CAD risk associated with the presence of the 242T allele and both traditional risk factors was approximately 500% greater than the risk predicted by assuming additivity of effects (synergy index, 5.08).

CONCLUSION

The 242T allele interacts with cigarette smoking and hypercholesterolemia to increase the risk of CAD; this risk is probably associated with the cumulative/synergistic effect of the 242T allele and both the traditional risk factors.