The effect of p22-PHOX (CYBA) polymorphisms on premature coronary artery disease (≤ 40 years of age)

Summary

Acute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a logadditive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45–0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3–0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).

Keywords

Premature coronary artery disease - myocardial infarction - p22-PHOX (CYBA) - ROS - epidemiology

• References

• 1 Fournier JA, Cabezon S, Cayuela A. et al. Long-term prognosis of patients having acute myocardial infarction when </=40 years of age. Am J Cardiol 2004; 94: 989-992.
• 2 Jalowiec DA, Hill JA. Myocardial infarction in the young and in women. Cardiovasc Clin 1989; 20: 197-206.
• 3 Wiesbauer F, Blessberger H, Azar D. et al. Familial-combined hyperlipidaemia in very young myocardial infarction survivors (< or =40 years of age). Eur Heart J 2009; 30: 1073-1079.
• 4 Wiesbauer F, Blessberger H, Goliasch G. et al. Elevated risk of myocardial infarction in very young immigrants from former Yugoslavia. Eur J Epidemiol 2009; 24: 691-696.
• 5 Soccio M, Toniato E, Evangelista V. et al. Oxidative stress and cardiovascular risk: the role of vascular NAD(P)H oxidase and its genetic variants. Eur J Clin Invest 2005; 35: 305-314.
• 6 San Jose G, Moreno MU, Olivan S. et al. Functional effect of the p22phox –930A/G polymorphism on p22phox expression and NADPH oxidase activity in hypertension. Hypertension 2004; 44: 163-169.
• 7 Zalba G, San Jose G, Beaumont FJ. et al. Polymorphisms and promoter overactivity of the p22(phox) gene in vascular smooth muscle cells from spontaneously hypertensive rats. Circ Res 2001; 88: 217-222.
• 8 Thygesen K, Alpert JS, White HD. et al. Universal definition of myocardial infarction. Circulation 2007; 116: 2634-2653.
• 9 Levantesi G, Macchia A, Marfisi R. et al. Metabolic syndrome and risk of cardiovascular events after myocardial infarction. J Am Coll Cardiol 2005; 46: 277-283.
• 10 Moreno MU, San Jose G, Orbe J. et al. Preliminary characterisation of the promoter of the human p22(phox) gene: identification of a new polymorphism associated with hypertension. FEBS Lett 2003; 542: 27-31.
• 11 Rothman K, Greenland S. Modern Epidemiology. 1998: 147-162.
• 12 Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J Royal Stat Soc 1995; 57: 289-300.
• 13 Inoue N, Kawashima S, Kanazawa K. et al. Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease. Circulation 1998; 97: 135-137.
• 14 Dupont W. Power calculations for matched case-control studies. Biometrics 1988; 44: 1157-1168.
• 15 Guzik TJ, West NE, Black E. et al. Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. Circulation 2000; 102: 1744-1747.
• 16 Cai H, Duarte N, Wilcken DE. et al. NADH/NADPH oxidase p22 phox C242T polymorphism and coronary artery disease in the Australian population. Eur J Clin Invest 1999; 29: 744-748.
• 17 Hayaishi-Okano R, Yamasaki Y, Kajimoto Y. et al. Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes. Diabetes Care 2003; 26: 458-463.
• 18 Gardemann A, Mages P, Katz N. et al. The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals. Atherosclerosis 1999; 145: 315-323.
• 19 Li A, Prasad A, Mincemoyer R. et al. Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function. Am J Med Genet 1999; 86: 57-61.
• 20 Saha N, Sanghera DK, Kamboh MI. The p22 phox polymorphism C242T is not associated with CHD risk in Asian Indians and Chinese. Eur J Clin Invest 1999; 29: 999-1002.
• 21 Di Castelnuovo A, Soccio M, Iacoviello L. et al. The C242T polymorphism of the p22phox component of NAD(P)H oxidase and vascular risk. Two case-control studies and a meta-analysis. Thromb Haemost 2008; 99: 594-601.
• 22 Zahler S, Kupatt C, Becker BF. Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha. FASEB J 2000; 14: 555-564.
• 23 Becker LB. New concepts in reactive oxygen species and cardiovascular reper-fusion physiology. Cardiovasc Res 2004; 61: 461-470.
• 24 Tang H, Hao Q, Rutherford SA. et al. Inactivation of SRC family tyrosine kinases by reactive oxygen species in vivo. J Biol Chem 2005; 280: 23918-23925.