The C242T polymorphism of the p22phox component of NAD (P)H oxidase and vascular risk

Augusto Di Castelnuovo; Manola Soccio; Licia Iacoviello; Virgilio Evangelista; Agostino Consoli; Diego Vanuzzo; Silvia Diviacco; Marisa Carluccio; Lucia Rignanese; Raffaele De Caterina

doi:10.1160/TH07-08-0480

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(03): 594-601
DOI: 10.1160/TH07-08-0480

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

The C₂₄₂T polymorphism of the p22phox component of NAD (P)H oxidase and vascular risk

Two case-control studies and a meta-analysis

Authors

Augusto Di Castelnuovo

¹Laboratory of Genetic and Environmental Epidemiology, Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy
Manola Soccio

²Institute of Cardiology

³Center of Excellence on Aging, “G. d’Annunzio University”, Chieti, Italy
Licia Iacoviello

¹Laboratory of Genetic and Environmental Epidemiology, Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy
Virgilio Evangelista

⁴Consorzio Mario Negri Sud, Santa Maria Imbaro
Agostino Consoli

³Center of Excellence on Aging, “G. d’Annunzio University”, Chieti, Italy
Diego Vanuzzo

⁵Cardiovascular Prevention Center, ASS 4 and Agenzia Regionale della Sanità del Friuli- Venezia Giulia, Udine
Silvia Diviacco

⁵Cardiovascular Prevention Center, ASS 4 and Agenzia Regionale della Sanità del Friuli- Venezia Giulia, Udine
Marisa Carluccio

⁶CNR Institute of Clinical Physiology, Pisa, Italy
Lucia Rignanese

²Institute of Cardiology

³Center of Excellence on Aging, “G. d’Annunzio University”, Chieti, Italy
Raffaele De Caterina

²Institute of Cardiology

³Center of Excellence on Aging, “G. d’Annunzio University”, Chieti, Italy

⁶CNR Institute of Clinical Physiology, Pisa, Italy

Abstract

Summary

NAD(P)H oxidase is a prominent source of reactive oxygen species in the vasculature.Vascular NAD(P)H oxidase is comprised of several subunits, one of which, p22phox, is encoded by a gene exhibiting several allelic variants. Here the C₂₄₂T nucleotide transition has been found to alter superoxide anion production and associated with an altered risk of coronary artery disease (CAD). We assessed the role of this variant in two casecontrol studies, and performed a meta-analysis of previously reported investigations relating it to vascular risk. Population I was comprised of 492 subjects with type 2 diabetes, with or without macrovascular disease,matched for age,sex,and duration of diabetes. Population II was comprised of 158 subjects with or without either CAD or cerebro-vascular disease, and matched for age,sex,smoking status,weight category and the presence of hypertension, dyslipidemia, and diabetes. Our findings were metaanalyzed together with additional studies retrieved from the literature. The C₂₄₂T polymorphism distribution did not differ between cases and controls in populations I and II both at univariate and multivariate analyses, and this was confirmed in a metaanalysis with || previously published populations. The metaanalysis, however, suggested a protective role of the T allele on CAD as an end point in Asian populations. In conclusion, these data suggest a significant heterogeneity for a modulating role of the T allele in the C₂₄₂T polymorphism of p22-phox for the occurrence of CAD across ethnicities,with the absence of a significant effect in Caucasians.

Keywords

NADPH oxidase - p22-phox - reactive oxygen species - gene polymorphisms - meta-analysis - vascular risk

Full Text

References

References
1 Pratico D, Iuliano L, Mauriello A. et al. Localization of distinct F2-isoprostanes in human atherosclerotic lesions. J Clin Invest 1997; 100: 2028-2034.
2 Martinet W, Kockx MM. Apoptosis in atherosclerosis: focus on oxidized lipids and inflammation. Curr Opin Lipidol 2001; 12: 535-541.
3 Liao F, Andalibi A, Qiao JH. et al. Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest 1994; 94: 877-884.
4 Mugge A, Elwell JH, Peterson TE. et al. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991; 69: 1293-1300.
5 Keaney JF, Jr. Xu A, Cunningham D. et al. Dietary probucol preserves endothelial function in cholesterolfed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest 1995; 95: 2520-2529.
6 Rajagopalan S, Meng XP, Ramasamy S. et al. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrixmetalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 1996; 98: 2572-2579.
7 Griendling KK, Minieri CA, Ollerenshaw JD. et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994; 74: 1141-1148.
8 De Caterina R. Endothelial dysfunctions: common denominators in vascular disease. Curr Opin Lipidol 2000; 11: 9-23.
9 Griendling KK, Ushio-Fukai M. Redox control of vascular smooth muscle proliferation. J Lab Clin Med 1998; 132: 9-15.
10 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.
11 Ushio-Fukai M, Zafari AM, Fukui T. et al. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem 1996; 271: 23317-23321.
12 Sorescu D, Weiss D, Lassegue B. et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002; 105: 1429-1435.
13 Kalinina N, Agrotis A, Tararak E. et al. Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2002; 22: 2037-2043.
14 Dinauer MC, Pierce EA, Bruns GA. et al. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome- negative autosomal recessive chronic granulomatous disease. J Clin Invest 1990; 86: 1729-1737.
15 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.
16 Ciccarone E, Di Castelnuovo A, Salcuni M. et al. on behalf of the GENDIABE investigators. A high score Mediterranean dietary pattern is associated with a reduced risk of peripheral arterial disease in Italian patients with type 2 diabetes. J Thromb Haemost 2003; 1: 1744-1752.
17 World Health Organization. WHO MONICA Manual. Geneva: World Health Organization; 1998-1999.
18 Feruglio GA, Vanuzzo D, Pilotto L. The Martignacco Project. Comprehensive Cardiovascular Community Control Programmes in Europe. Copenhagen, DK: WHO Regional Office for Europe, Euro Reports and Studies; 1988: 52-58.
19 Rose GA, Blackburn HW. Cardiovascular Survey Methods. Geneva, CH: 1968
20 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
21 Cahilly C, Ballantyne CM, Lim DS. et al. A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis. Circ Res 2000; 86: 391-395.
22 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.
23 SAS Institute Inc. SAS/STAT User’s Guide. Version 8.1 Cary, NC: 1989
24 Martin DO, Austin H. Exact estimates for a rate ratio. Epidemiology 1996; 7: 29-33.
25 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.
26 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.
27 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.
28 Yamada Y, Izawa H, Ichihara S. et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 2002; 347: 1916-1923.
29 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.
30 Krex D, Ziegler A, Konig IR. et al. Polymorphisms of the NADPH oxidase P22PHOX gene in a Caucasian population with intracranial aneurysms. Cerebrovasc Dis 2003; 16: 363-368.
31 Matsunaga S, Maruyama T, Yamada S. et al. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) P22 Phox C242T gene polymorphism in type 1 diabetes. Ann NY Acad Sci 2003; 1005: 324-327.
32 Morgan TM, Krumholz HM, Lifton RP. et al. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. J Am Med Assoc 2007; 297: 1551-1561.
33 Guzik TJ, Mussa S, Gastaldi D. et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002; 105: 1656-1662.
34 Ito D, Murata M, Watanabe K. et al. C242T polymorphism of NADPH oxidase p22 PHOX gene and ischemic cerebrovascular disease in the Japanese population. Stroke 2000; 31: 936-939.
35 Renner W, Schallmoser K, Gallippi P. et al. C242T polymorphism of the p22 phox gene is not associated with peripheral arterial occlusive disease. Atherosclerosis 2000; 152: 175-179.
36 Spence MS, McGlinchey PG, Patterson CC. et al. Investigation of the C242T polymorphism of NAD(P)H oxidase p22 phox gene and ischaemic heart disease using family-based association methods. Clin Sci (Lond) 2003; 105: 677-682.
37 Azumi H, Inoue N, Takeshita S. et al. Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation 1999; 100: 1494-1498.
38 Schneider MP, Hilgers KF, Huang Y. et al. The C242T p22phox polymorphism and endothelium-dependent vasodilation in subjects with hypercholesterolaemia. Clin Sci (Lond) 2003; 105: 97-103.
39 Wyche KE, Wang SS, Griendling KK. et al. C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. Hypertension 2004; 43: 1246-1251.