Advertisement

A novel study to examine the association of PCSK9 rs505151 polymorphism and coronary artery disease in north Indian population

  • S. Reddy
  • Naindeep Kaur
  • Jagtar Singh
Research Article
  • 5 Downloads

Abstract

There is a drastic increase in the number of people suffering from coronary artery disease (CAD) worldwide with Indians being no exception. Being a developing country and experiencing a dramatic shift in lifestyle and eating habits, urbanization and industrialization, all these factors have collectively predisposed the Indian population towards CAD and the prevalence data are quite alarming. Genetic studies have disclosed the role of genes in CAD susceptibility and severity. One such gene is proprotein convertase subtilisin/kexin type 9 (PCSK9) which is sought to modulate the cholesterol levels and hence, has implications in CAD. We aim to explore the association of PCSK9 A/G (rs505151) polymorphism and hence, the susceptibility towards CAD in the north Indian population. Five-hundred angiographically confirmed CAD patients and 500 healthy individuals as control were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis revealed a significant association with the G allele with odds ratio (OR)=1.50, 95% confidence interval (CI)=1.22–1.85 and P=0.000. Also, a strong association was observed for CAD risk with OR=1.590, 95% CI=1.106–2.284 and P=0.012. However, the homozygous GG mutant genotype was found to be completely absent from our population. Analysis of the dominant model also revealed an association with CAD risk. Our work demonstrated for the first time the association of PCSK9 A/G (rs505151) polymorphism with CAD risk in the north Indian population.

Keyword

genetic polymorphism north Indian population coronary artery disease polymerase chain reaction-restriction fragment length polymorphism low density lipoprotein receptor 

Notes

Acknowledgements

All the authors are grateful to the participants (control subjects and patients involved in this study.

References

  1. Abboud S., Karhunen P. J., Lütjohann D., Goebeler S., Luoto T., Friedrichs S. et al. 2007 Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS One 2, e1043.CrossRefGoogle Scholar
  2. Abdel-Maksoud M. F., Eckel R. H., Hamman R. F. and Hokanson J. E. 2012 Risk of coronary heart disease is associated with triglycerides and high-density lipoprotein cholesterol in women and non-high-density lipoprotein cholesterol in men. J. Clin. Lipidol. 6, 374–381.CrossRefGoogle Scholar
  3. Adifadel M., Varret M., Rabés J., Allard D., Ouguerram K. and Devillers M. 2003 Mutations in PCSK9 cause autosomal dominant hipercolesterolemia. Nat. Genet. 34, 154.CrossRefGoogle Scholar
  4. ArulJothi K., Whitthall R., Futema M., Humphries S., George M., Elangovan S. et al. 2016 Molecular analysis of the LDLR gene in coronary artery disease patients from the Indian population. Clin. Biochem. 49, 669–674.CrossRefGoogle Scholar
  5. Aung L. H. H., Yin R. X., Miao L., Hu X. J., Yan T. T., Cao X. L. et al. 2011 The proprotein convertase subtilisin/kexin type 9 gene E670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids Health Dis. 10, 5.CrossRefGoogle Scholar
  6. Chen S. N., Ballantyne C. M., Gotto Jr A. M., Tan Y., Willerson J. T. and Marian A. J. 2005 A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J. Am. Coll. Cardiol. 45, 1611–1619.CrossRefGoogle Scholar
  7. Deloukas P., Kanoni S., Willenborg C., Farrall M., Assimes T. L., Thompson J. R. et al. 2013 Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25.CrossRefGoogle Scholar
  8. Evans D. and Beil F. U. 2006 The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med. Genet. 7, 66.CrossRefGoogle Scholar
  9. Ferri N., Tibolla G., Pirillo A., Cipollone F., Mezzetti A., Pacia S. et al. 2012 Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 220, 381–386.CrossRefGoogle Scholar
  10. Gotto A. M. and Moon J. E. 2012 Management of cardiovascular risk: the importance of meeting lipid targets. Am. J. Cardiol. 110, 3A–14A.CrossRefGoogle Scholar
  11. Gupta R., Guptha S., Sharma K. K., Gupta A. and Deedwania P. 2012 Regional variations in cardiovascular risk factors in India: India heart watch. WJC 4, 112.CrossRefGoogle Scholar
  12. Holla Ø. L., Cameron J., Tveten K., Strøm T. B., Berge K. E., Laerdahl J. K. et al. 2011 Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors. J. Lipid Res. 52, 1787–1794.CrossRefGoogle Scholar
  13. Huang C. C., Fornage M., Lloyld-Jones D. M., Wei G. S., Boerwinkle E. and Liu K. 2009 Longitudinal association of PCSK9 sequence variations with LDL-cholesterol levels: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Circ. Cardiovasc. Genet. 108, 828467.Google Scholar
  14. Hsu L. A, Teng M. S., Ko Y. L., Chang C. J., Wu S., Wang C. L. et al. 2009 The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan. Clin. Chem. Lab. Med. 47, 154–158.CrossRefGoogle Scholar
  15. Joshi P., Islam S., Pais P., Reddy S., Dorairaj P., Kazmi K. et al. 2007 Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 297, 286–294.CrossRefGoogle Scholar
  16. Kotowski I. K., Pertsemlidis A., Luke A., Cooper R. S., Vega G. L., Cohen J. C. et al. 2006 A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410–422.CrossRefGoogle Scholar
  17. Lagace T. A., Curtis D. E., Garuti R., McNutt M. C., Park S. W., Prather H. B. et al. 2006 Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest. 116, 2995–3005.CrossRefGoogle Scholar
  18. Lalanne F., Lambert G., Amar M. J., Chétiveaux M., Zaïr Y., Jarnoux A. L. et al. 2005. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J. Lipid Res. 46, 1312–1319.CrossRefGoogle Scholar
  19. Lambert G., Charlton F., Rye K. A. and Piper D. E. 2009 Molecular basis of PCSK9 function. Atherosclerosis 203, 1–7.CrossRefGoogle Scholar
  20. LeBlanc M., Zuber V., Andreassen B. K., Witoelar A., Zeng L., Bettella F. et al. 2015 Identifying novel gene variants in coronary artery disease and shared genes with several cardiovascular risk factors. Circ. Res. 115, 306629.Google Scholar
  21. Maiti S., Biswas P., Banerjee S., Jana N. K. 2017 Study of the association of PCSK9/Eam1104I gene polymorphism with plasma lipid concentration and CAD in West Bengal population. Int. J. Life Sci. Sci. Res. 3, 1271–1277.Google Scholar
  22. Maxwell K. N. and Breslow J. L. 2004 Adenoviral-mediated expression of PCSK9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl. Acad. Sci. USA 101, 7100–7105.CrossRefGoogle Scholar
  23. Meng Y. and Liu Z. 2011 A study on the correlation between E670G polymorphism of PCSK9 gene and coronary artery disease in the Guangdong population. J. Trop. Med. 11, 137–140.Google Scholar
  24. Messner B. and Bernhard D. 2014 Smoking and cardiovascular disease significance: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 34, 509–515.CrossRefGoogle Scholar
  25. Mo Y., Li W., Zhong Y. and Zhang X. 2015 Dongguan Han patients with coronary artery PCSK9 gene SNP and its prognosis. Int. J. Lab. Med. 12, 1725–1727.Google Scholar
  26. Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C. F., Huang Y. et al. 2003 Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch. Biochem. Biophys. 420, 55–67.CrossRefGoogle Scholar
  27. Norata G. D., Garlaschelli K., Grigore L., Raselli S., Tramontana S., Meneghetti F. et al. 2010 Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis 208, 177–182.CrossRefGoogle Scholar
  28. Park S. W., Moon Y. A. and Horton J. D. 2004 Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279, 50630–50638.CrossRefGoogle Scholar
  29. Polisecki E., Peter I., Robertson M., McMahon A. D., Ford I., Packard C. et al. 2008 Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. Atherosclerosis 200, 95–101.CrossRefGoogle Scholar
  30. Prabhakaran D., Jeemon P. and Roy A. 2016 Cardiovascular diseases in India: current epidemiology and future directions. Circulation 133, 1605–1620.CrossRefGoogle Scholar
  31. Ramasamy I. 2014 Recent advances in physiological lipoprotein metabolism. CCLM 52, 1695–1727.CrossRefGoogle Scholar
  32. Rashid S., Curtis D. E., Garuti R., Anderson N. N., Bashmakov Y., Ho Y. et al. 2005. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking PCSK9. Proc. Natl. Acad. Sci. USA 102, 5374–5379.CrossRefGoogle Scholar
  33. Rousselet E., Marcinkiewicz J., Kriz J., Zhou A., Hatten M. E., Prat A. et al. 2011 PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J. Lipid Res. 52, 1383–1391.CrossRefGoogle Scholar
  34. Saely C. H. and Drexel H. 2013 Is type 2 diabetes really a coronary heart disease risk equivalent?Vasc. Pharmacol. 59, 11–18.CrossRefGoogle Scholar
  35. Sanchis-Gomar F., Perez-Quilis C., Leischik R. and Lucia A. 2016 Epidemiology of coronary heart disease and acute coronary syndrome. Ann. Transl. Med. 4, 13.CrossRefGoogle Scholar
  36. Scartezini M., Hubbart C., Whittall R. A., Cooper J. A., Neil A. H. and Humphries S. E. 2007 The PCSK9 gene R46 L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy UK men. Clin. Sci. 113, 435–441.CrossRefGoogle Scholar
  37. Seidah N. G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S. B., Stifani S. et al. 2003 The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA 100, 928–933.CrossRefGoogle Scholar
  38. Slimani A., Harira Y., Trabelsi I., Jomaa W., Maatouk F., Hamda K. B. et al. 2014 Effect of E670G polymorphism in PCSK9 gene on the risk and severity of coronary heart disease and ischemic stroke in a Tunisian cohort. J. Mol. Neurosci. 53, 150–157.CrossRefGoogle Scholar
  39. Soutar A. K. and Naoumova R. P. 2007 Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat. Rev. Cardiol. 4, 214.CrossRefGoogle Scholar
  40. Teslovich T. M., Musunuru K., Smith A. V., Edmondson A. C., Stylianou I. M., Koseki M. et al. 2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707.CrossRefGoogle Scholar
  41. Tsai C. W., North K. E., Tin A., Haack K., Franceschini N., Saroja Voruganti V. et al. 2015 Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians. J. Clin. Endocrinol. Metab. 100, E345–E349.CrossRefGoogle Scholar
  42. Tveten K., Holla Ø. L., Cameron J., Strøm T. B., Berge K. E., Laerdahl J. K. et al. 2011 Interaction between the ligand-binding domain of the LDL receptor and the C-terminal domain of PCSK9 is required for PCSK9 to remain bound to the LDL receptor during endosomal acidification. Hum. Mol. Genet. 21, 1402–1409.CrossRefGoogle Scholar
  43. Xavier D., Pais P., Devereaux P., Xie C., Prabhakaran D., Reddy K. S. et al. 2008 Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 371, 1435–1442.CrossRefGoogle Scholar
  44. Zhang L., Song K., Zhu M., Shi J., Zhang H., Xu L. et al. 2016 Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke. Int. J. Neurosci. 126, 675–680.PubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  1. 1.Department of CardiologyPostgraduate Institute of Medical Education and ResearchChandigarh India
  2. 2.Department of BiotechnologyPanjab UniversityChandigarh India

Personalised recommendations