Indian Journal of Medical Biochemistry

Register      Login

VOLUME 24 , ISSUE 3 ( September-December, 2020 ) > List of Articles

Original Article

Association of Dimethylarginine Dimethylaminohydrolase 2 (DDAH-2 1154 C > A) Gene Polymorphism with Coronary Artery Disease

B Vinodh Kumar, K Ramadevi

Citation Information : Kumar BV, Ramadevi K. Association of Dimethylarginine Dimethylaminohydrolase 2 (DDAH-2 1154 C > A) Gene Polymorphism with Coronary Artery Disease. Indian J Med Biochem 2020; 24 (3):99-103.

DOI: 10.5005/jp-journals-10054-0163

License: CC BY-NC 4.0

Published Online: 01-12-2020

Copyright Statement:  Copyright © 2020; The Author(s).


Background: Coronary artery disease is one of the most common causes of death. The initiation of atherosclerosis is due to endothelial dysfunction and is mainly due to decreased nitric oxide bioavailability. The nitric oxide is synthesized from L-arginine by endothelial nitric oxide synthase. The nitric oxide synthase inhibitor has been identified namely asymmetric dimethylarginine (ADMA). The major route of degradation of ADMA is by the dimethylarginine dimethylaminohydrolase enzymes. The gene silencing studies in rats have shown that the dimethylarginine dimethylaminohydrolase (DDAH) enzyme through the degradation of ADMA, regulates the function of nitric oxide synthase. Therefore, this study was undertaken to find the association of DDAH-2 gene polymorphisms with coronary artery disease. Aims and objectives: The objective of the study is to find out the association of DDAH-2 gene (1151 C/A) polymorphism with coronary artery disease. To estimate the serum nitric oxide levels and find its relationship with the above gene polymorphism. Materials and methods: Case-control study. One hundred cases of coronary artery disease in the age group between 35 years and 60 years old verified by coronary angiogram having >50% stenosis of at least one of the major coronary arteries were randomly recruited. Cases may be with or without risk factors like smoking, alcohol, and hypertension. Age, sex, and risk factors matched 100 controls who had no clinical evidence of coronary artery disease were selected. Assessment of DDAH-2 (1154 C > A) gene polymorphism was done by TaqMan assay using real-time PCR and confirmation of SNP genotypes was done by Sanger sequencing. Results: AA genotype of DDAH-2 was significantly higher among cases (29%) when compared with controls (14%) with a statistically significant p value of 0.009. The odds ratio of 2.1 showed that subjects with the A+ allele carry a higher risk for coronary artery disease when compared with the A allele. The serum nitric oxide was significantly lower in the AA genotype when compared with the CA and CC genotypes of the DDAH2 gene. Conclusion: In this study, there is a good association of the A allele of DDAH-2 with the development of coronary artery disease (odds ratio of 2.19). Thus, A allele may be an independent risk factor for coronary artery disease. Multiple logistic regression predicts AA genotype as a significant and independent predictor of coronary artery disease.

  1. Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992;340(8833):1430–1432. DOI: 10.1016/0140-6736(92)92621-L.
  2. Panza JA, Quyyumi AA, Brush JrJE, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Eng J Med 1990;323(1):22–27. DOI: 10.1056/NEJM199007053230105.
  3. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Colle Cardiol 1996;27(3):567–574. DOI: 10.1016/0735-1097(95)00522-6.
  4. Leone A, Moncada S, Vallance P, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339(8793):572–575. DOI: 10.1016/0140-6736(92)90865-Z.
  5. Vallance P, Leone A, Calver A, et al. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovascu Pharmacol 1992;20:S60–S62. DOI: 10.1097/00005344-199204002-00018.
  6. Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovascu Res 1999;43(3):542–548. DOI: 10.1016/S0008-6363(99)00162-5.
  7. Leiper JM, Maria JS, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999;343(1):209–214. DOI: 10.1042/bj3430209.
  8. Tran CT, Fox MF, Vallance P, et al. Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 2000;68(1):101–105. DOI: 10.1006/geno.2000.6262.
  9. Bogumil R, Knipp M, Fundel SM, et al. Characterization of dimethylargininase from bovine brain: evidence for a zinc binding site. Biochemistry 1998;37(14):4791–4798. DOI: 10.1021/bi972312t.
  10. Knipp M, Charnock JM, Garner CD, et al. Structural and functional characterization of the Zn (II) site in dimethylargininase-1 (DDAH-1) from bovine brain Zn (II) release activates DDAH-1. J Biolog Chemis 2001;276(44):40449–40456. DOI: 10.1074/jbc.M104056200.
  11. Wang D, Gill PS, Chabrashvili T, et al. Isoform-specific regulation by NG, N G-dimethylarginine dimethylaminohydrolase of rat serum asymmetric dimethylarginine and vascular endothelium-derived relaxing factor/NO. Circulat Res 2007;101(6):627–635. DOI: 10.1161/CIRCRESAHA.107.158915.
  12. Jones LC, Hingorani AD. Genetic regulation of endothelial function. Heart 2005;91(10):1275–1277. DOI: 10.1136/hrt.2005.061325.
  13. Gad MZ, Hassanein SI, Abdel-Maksoud SM, et al. Association of DDAH2 gene polymorphism with cardiovascular disease in Egyptian patients. J Genet 2011;90(1):161. DOI: 10.1007/s12041-011-0043-4.
  14. Maas R, Erdmann J, Lüneburg N, et al. Polymorphisms in the promoter region of the dimethylarginine dimethylaminohydrolase 2 gene are associated with prevalence of hypertension. Pharmacologi Res 2009;60(6):488–493. DOI: 10.1016/j.phrs.2009.07.013.
  15. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 1990;36(8):1440–1443. DOI: 10.1093/clinchem/36.8.1440.
  16. Jones LC, Tran CT, Leiper JM, et al. Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem Biophysi Res Communicati 2003;310(3):836–843. DOI: 10.1016/j.bbrc.2003.09.097.
  17. Schnabel R, Blankenberg S, Lubos E, et al. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the athero gene study. Circulat Res 2005;97(5):e53–e59. DOI: 10.1161/01.RES.0000181286.44222.61.
  18. Bouras G, Deftereos S, Tousoulis D, et al. Dimethylarginine (ADMA): a promising biomarker for cardiovascular disease? Curr Top Med Chemis 2013;13(2):180–200. DOI: 10.2174/1568026611313020007.
  19. Zoccali C. Traditional and emerging cardiovascular and renal risk factors: an epidemiologic perspective. Kidney Int 2006;70(1):26–33. DOI: 10.1038/
  20. Xuan C, Xu LQ, Tian QW, et al. Dimethylarginine dimethylaminohydrolase 2 (DDAH 2) gene polymorphism, asymmetric dimethylarginine (ADMA) concentrations, and risk of coronary artery disease: a case-control study. Scienti Rep 2016;6(1):1–6. DOI: 10.1038/srep33934.
  21. Mannino GC, Pezzilli S, Averta C, et al. A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients. Cardiovascu Diabetol 2019;18(1):102. DOI: 10.1186/s12933-019-0906-1.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.