Skip to main content

Advertisement

Log in

Association of CYP2C8, CYP2C9 and CYP2J2 gene polymorphisms with myocardial infarction in South Indian population

  • Original research article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Cardiovascular diseases (CVDs) are the major cause of mortality and morbidity worldwide. Myocardial infarction (MI) is a complex multi-factorial, polygenic disorder arising from an interaction between genetic makeup of individuals and various environmental factors. CYP2C8, CYP2C9 and CYP2J2 gene involved in the metabolism of arachidonic acid, generates epoxyeicosatrienoic acids (EETs) that mediate dilation of coronary arteries improving post-ischemic cardiac contractile function, reduce vascular inflammation, and increase intravascular fibrinolysis. The study is aimed at analyzing the association of CYP2C8, CYP2C9 and CYP2J2 gene polymorphisms and MI risk in the South Indian population.

Methods

This retrospective study consisted of 287 MI patients, 279 risk control patients and 321 healthy individuals. Blood samples were collected from all the subjects and DNA was isolated using standard phenol–chloroform method. Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and real time-polymerase chain reaction (RT-PCR) methods were used for genotyping. To test the potential independent association between polymorphisms and the risk of MI, Multiple-logistic regression analysis was performed.

Results

Our findings displayed a significant association between CYP2J2*7 (p = 0.04; OR = 2.0) polymorphism and MI while comparing cases with to risk controls. We did not observe any association of CYP2C8*2, CYP2C8*3, CYP2C9*2 and CYP2C9*3 with MI.

Conclusion

Our results suggest that individuals with any conventional risk factor for MI along with CYP2J2*7 variant allele may be predisposed to risk of MI in South Indian population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:442.

    Article  Google Scholar 

  2. World Health Organization. Global atlas on cardiovascular disease prevention and control. Geneva: World Health Organization; 2011.

    Google Scholar 

  3. Node K, Ruan XL, Dai J, Yang SX, Graham L, Zeldin DC, et al. Activation of Galpha s mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids. J Biol Chem 2001;276:15983–89.

    Article  CAS  Google Scholar 

  4. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 2002;82:131–85.

    Article  CAS  Google Scholar 

  5. Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS, Liao JK. Inhibition of vascular smooth muscle cell migration by cytochrome P450 epoxygenase-derived eicosanoids. Circ Res 2002;90:1020–7.

    Article  CAS  Google Scholar 

  6. Wang H, Lin L, Jiang J, Wang Y, Lu ZY, Bradbury JA, et al. Up-regulation of endothelial nitric-oxide synthase by endothelium-derived hyperpolarizing factor involves mitogen-activated protein kinase and protein kinase C signaling pathways. J Pharmacol Exp Ther 2003;307:753–64.

    Article  CAS  Google Scholar 

  7. Rodrigues AD. Impact of cyp2c9 genotype on pharmacokinetics: are all cyclo-oxygenase inhibitors the same? Drug Metab Dispos 2005;33:1567–75.

    Article  CAS  Google Scholar 

  8. Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ. Trimethoprim and sulfamethoxazole are selective inhibitors of cyp2c8 and cyp2c9, respectively. Drug Metab Dispos 2002;30:631–5.

    Article  CAS  Google Scholar 

  9. Lee CA, Jones 3rd JP, Katayama J, Kaspera R, Jiang Y, Freiwald S, et al. Identifying a selective substrate and inhibitor pair for the evaluation of cyp2j2 activity. Drug Metab Dispos 2012;40:943–51.

    Article  CAS  Google Scholar 

  10. Xu X, Zhang XA, Wang DW. The roles of CYP450 epoxygenases and metabolites, epoxyeicosatrienoic acids, in cardiovascular and malignant diseases. Adv Drug Deliv Rev 2011;63:597–609.

    Article  CAS  Google Scholar 

  11. Arun Kumar AS, Chakradhara Rao US, Umamaheswaran G, Ramu P, Kesavan R, Shewade DG, et al. Haplotype structures of common variants of CYP2C8, CYP2C9, and ADRB1 genes in a South Indian population. Genet Test Mol Biomarkers 2011;15:407–13.

    Article  CAS  Google Scholar 

  12. Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001;11:597–607.

    Article  CAS  Google Scholar 

  13. Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I, et al. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 1999;401:493–7.

    Article  CAS  Google Scholar 

  14. Wu X, Zuo J, Guo T, Yuan L. CYP2C8 polymorphism frequencies among Han, Uighur, Hui, and Mongolian Chinese populations. Genet Test Mol Biomarkers 2013;17:104–8.

    Article  CAS  Google Scholar 

  15. Rosemary J, Surendiran A, Rajan S, Shashindran CH, Adithan C. Influence of the CYP2C9 and CYP2C19 polymorphisms on phenytoin hydroxylation in healthy individuals from South India. Indian J Med Res 2006;123:665–70.

    CAS  PubMed  Google Scholar 

  16. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353:717–9.

    Article  CAS  Google Scholar 

  17. Liu PY, Li YH, Chao TH, Wu HL, Lin LJ, Tsai LM, et al. Synergistic effect of Cytochrome P450 epoxygenase CYP2J2*7 polymorphism with smoking on the onset of premature myocardial infarction. Atherosclerosis 2007;195:199–206.

    Article  CAS  Google Scholar 

  18. Yasar U, Bennet AM, Eliasson E, Lundgren S, Wiman B, De Faire U, et al. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics 2003;13:715–20.

    Article  CAS  Google Scholar 

  19. Arun Kumar AS, Umamaheswaran G, Padmapriya R, Balachandar J, Adithan C. Endothelial nitric oxide synthase gene polymorphisms and the risk of acute myocardial infarction in a South Indian population. Mol Biol Rep 2013;40: 1275–81.

    Article  CAS  Google Scholar 

  20. Spiecker M, Liao J. Cytochrome P450 epoxygenase CYP2J2 and the risk of coronary artery disease. Trends Cardiovasc Med 2006;16:204–8.

    Article  CAS  Google Scholar 

  21. Fleming I, Michaelis UR, Bredenkotter D, Fisslthaler B, Dehghani F, Brandes RP, et al. Endothelium-derived hyperpolarizing factor synthase (Cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res 2001;88:44–51.

    Article  CAS  Google Scholar 

  22. Zhang Y, Oltman CL, Lu T, Lee HC, Dellsperger KC, VanRollins M. EET homologs potently dilate coronary microvessels and activate BK(Ca) channels. Am J Physiol Heart Circ Physiol 2001;280:2430–40.

    Article  Google Scholar 

  23. Marciante KD, Totah RA, Heckbert SR, Smith NL, Lemaitre RN, Lumley T, et al. Common variation in cytochrome P450 epoxygenase genes and the risk of incident nonfatal myocardial infarction and ischemic stroke. Pharmacogenet Genomics 2008;18:535–43.

    Article  CAS  Google Scholar 

  24. Spiecker M, Darius H, Hankeln T, Soufi M, Sattler AM, Schaefer JR, et al. Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2. Circulation 2004;110:2132–6.

    Article  CAS  Google Scholar 

  25. Hoffmann MM, Bugert P, Seelhorst U, Wellnitz B, Winkelmann BR, Boehm BO, et al. The 50G > T polymorphism in the promoter of the CYP2J2 gene in coronary heart disease: the Ludwigshafen risk and cardiovascular health study. Clin Chem 2007;53:539–40.

    Article  CAS  Google Scholar 

  26. Lee CR, North KE, Bray MS, Couper DJ, Heiss G, Zeldin DC. CYP2J2 and CYP2C8 polymorphisms and coronary heart disease risk: the atherosclerosis risk in communities (ARIC) study. Pharmacogenet Genomics 2007;17:349–58.

    Article  CAS  Google Scholar 

  27. Xu Y, Ding H, Peng J, Cui G, Liu L, Cianflone K, et al. Association between polymorphisms of CYP2J2 and EPHX2 genes and risk of coronary artery disease. Pharmacogenet Genomics 2011;21:489–94.

    Article  CAS  Google Scholar 

  28. Borgel J, Bulut D, Hanefeld C, Neubauer H, Mugge A, Epplen JT, et al. The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile. BMC Cardiovasc Disord 2008;8:41.

    Article  Google Scholar 

  29. Haschke-Becher E, Kirchheiner J, Trummer O, Grunbacher G, Kainz A, Boehm BO, et al. Impact of CYP2C8 and 2C9 polymorphisms on coronary artery disease and myocardial infarction in the LURIC cohort. Pharmacogenomics 2010;11: 1359–65.

    Article  CAS  Google Scholar 

  30. Visser LE, van Schaik RH, Jan Danser AH, Hofman A, Witteman JC, van Duijn CM, et al. The risk of myocardial infarction in patients with reduced activity of cytochrome P450 2C9. Pharmacogenet Genomics 2007;17:473–9.

    Article  CAS  Google Scholar 

  31. Dreisbach AW, Japa S, Sigel A, Parenti MB, Hess AE, Srinouanprachanh SL, et al. The prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension. Am J Hypertens 2005;18: 1276–81.

    Article  CAS  Google Scholar 

  32. Funk M, Endler G, Freitag R, Wojta J, Huber K, Mannhalter C, et al. CYP2C9*2 and CYP2C9*3 alleles confer a lower risk for myocardial infarction. Clin Chem 2004;50:2395–8.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Annan Sudarsan Arun Kumar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arun Kumar, A.S., Kumar, S.S., Umamaheswaran, G. et al. Association of CYP2C8, CYP2C9 and CYP2J2 gene polymorphisms with myocardial infarction in South Indian population. Pharmacol. Rep 67, 97–101 (2015). https://doi.org/10.1016/j.pharep.2014.08.010

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2014.08.010

Keywords

Navigation