Skip to main content

A Study of Associations Between rs9349379 (PHACTR1), rs2891168 (CDKN2B-AS), rs11838776 (COL4A2) and rs4880 (SOD2) Polymorphic Variants and Coronary Artery Disease in Iranian Population

Abstract

Recent genome-wide association studies reported the association of polymorphic alleles of PHACTR1 (rs9349379 (G)), CDDKN2B-AS1 (rs2891168 (G)), COL4A2 (rs11838776 (A)) and SOD2 (rs4880 (T)) with increased risk of coronary artery disease (CAD). The aim of our study was to assess the association of genetic variants with risk of CAD and its severity and in Southeast Iranian population. This study was examined in 250 CAD-suspected patients (mean age 53.49 ± 6.9 years) and 250 healthy individuals (mean age 52.96 ± 5.9 years). The Taqman SNP genotyping assay was used for genotyping of rs9349379 and rs2891168 variants. Tetra-primer Amplified refractory mutation system-PCR (Tetra-primer ARMS-PCR) was employed for rs11838776 and rs4880. Multivariate logistic regression analyses indicated that the G allele of rs9349379 and rs2891168 were associated with increased risk of CAD. The GG homozygous genotype of rs9349379 and rs2891168 had also been associated with risk of CAD. Additionally, the AG genotype of rs2891168 was associated with CAD. The significance of association of rs2891168 (G, GG, AG) increases with severity of CAD; but the rs9349379 (G, GG) have shown reverse association with severity of CAD. The genetic variants of COL4A2 (rs11838776) and SOD2 (rs4880) reflected no association with CAD in Southeast Iranian population. The findings of this study revealed that the PHACTR1 (rs9349379) and CDKN2B-AS1 (rs2891168) genetic variants might serve as genetic risk factor in CAD.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

References

  1. Abbasi M, Daneshpour MS, Hedayati M et al (2018) The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study. Nutr Metab 15:1–8. https://doi.org/10.1186/s12986-018-0264-0

    CAS  Article  Google Scholar 

  2. Adlam D, Olson TM, Combaret N et al (2019) Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection. J Am Coll Cardiol 73:58–66. https://doi.org/10.1016/j.jacc.2018.09.085

    CAS  Article  PubMed  Google Scholar 

  3. Aherrahrou R, Aherrahrou Z, Schunkert H, Erdmann J (2017) Coronary artery disease associated gene Phactr1 modulates severity of vascular calcification in vitro. Biochem Biophys Res Commun 491:396–402. https://doi.org/10.1016/j.bbrc.2017.07.090

    CAS  Article  PubMed  Google Scholar 

  4. Al-Ama M, Ahmed A (2018) U (2017) The CDKN2BAS polymorphism rs2891168 is associated with increased risk of myocardial infarction in a Saudi Arabian population. Middle East J Med Gene 7:39–45

    CAS  Google Scholar 

  5. Azeez SA, Al-Nafie AN, Al-Shehri A et al (2016) Intronic polymorphisms in the CDKN2B-AS1 gene are strongly associated with the risk of myocardial infarction and coronary artery disease in the Saudi population. Int J Mol Sci 17:395. https://doi.org/10.3390/ijms17030395

    CAS  Article  Google Scholar 

  6. Baoutina A, Dean RT, Jessup W (2000) Macrophages can decrease the level of cholesteryl ester hydroperoxides in low density lipoprotein. J Biol Chem 275:1635–1644. https://doi.org/10.1074/jbc.275.3.1635

    CAS  Article  PubMed  Google Scholar 

  7. Beaudoin M, Gupta RM, Won HH et al (2015) Myocardial infarction-associated SNP at 6p24 interferes with MEF2 binding and associates with PHACTR1 expression levels in human coronary arteries. Arterioscler Thromb Vasc Biol 35:1472–1479. https://doi.org/10.1161/ATVBAHA.115.305534

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Charmet R, Duffy S, Keshavarzi S et al (2018) Novel risk genes identified in a genome-wide association study for coronary artery disease in patients with type 1 diabetes. Cardiovasc Diabetol 17:61. https://doi.org/10.1186/s12933-018-0705-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Chen L, Qian H, Luo Z et al (2019) PHACTR1 gene polymorphism with the risk of coronary artery disease in Chinese Han population. Postgrad Med J 95:67–71. https://doi.org/10.1136/postgradmedj-2018-136298

    CAS  Article  PubMed  Google Scholar 

  10. Dandona S, Stewart AFR, Chen L et al (2010) Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol 56:479–486. https://doi.org/10.1016/j.jacc.2009.10.092

    CAS  Article  PubMed  Google Scholar 

  11. Decharatchakul N, Settasatian C, Settasatian N et al (2019) Association of genetic polymorphisms in SOD2, SOD3, GPX3, and GSTT1 with hypertriglyceridemia and low HDL-C level in subjects with high risk of coronary artery disease. PeerJ 7:e7407. https://doi.org/10.7717/peerj.7407

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ebrahimi M, Kazemi-Bajestani SMR, Ghayour-Mobarhan M, Ferns GAA (2011) Coronary artery disease and its risk factors status in iran: a review. Iran Red Crescent Med J 13:610–623

    CAS  Article  Google Scholar 

  13. Fang X, Weintraub NL, Rios CD et al (1998) Overexpression of human superoxide dismutase inhibits oxidation of low-density lipoprotein by endothelial cells. Circ Res 82:1289–1297. https://doi.org/10.1161/01.RES.82.12.1289

    CAS  Article  PubMed  Google Scholar 

  14. Ford T, Corcoran D, Padmanabhan S (2020) Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur Heart J 41:3239–3252

    CAS  Article  Google Scholar 

  15. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502. https://doi.org/10.1093/clinchem/18.6.499

    CAS  Article  PubMed  Google Scholar 

  16. Fujimaki T, Oguri M, Horibe H et al (2015) Association of a transcription factor 21 gene polymorphism with hypertension. Biomed Reports 3:118–122. https://doi.org/10.3892/br.2014.371

    Article  Google Scholar 

  17. Fujimoto H, Taguchi J, Imai Y (2008) Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease. Eur Hear J 29:1267–1274

    CAS  Article  Google Scholar 

  18. Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606

    CAS  Article  Google Scholar 

  19. Gong Y, Beitelshees AL, Cooper-DeHoff RM et al (2011) Chromosome 9p21 haplotypes and prognosis in white and black patients with coronary artery disease. Circ Cardiovasc Genet 4:169–178. https://doi.org/10.1161/CIRCGENETICS.110.959296

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Gori F, Specchia C, Pietri S et al (2010) Common genetic variants on chromosome 9p21 are associated with myocardial infarction and type 2 diabetes in an Italian population. BMC Med Genet 11:60. https://doi.org/10.1186/1471-2350-11-60

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Gupta RM, Hadaya J, Trehan A et al (2017) A genetic variant associated with five vascular diseases is a distal regulator of Endothelin-1 gene expression. Cell 170:522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Hager J, Kamatani Y, Cazier JB et al (2012) Genome-wide association study in a Lebanese cohort confirms PHACTR1 as a major determinant of coronary artery stenosis. PLoS ONE 7:e38663. https://doi.org/10.1371/journal.pone.0038663

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Howson JMM, Zhao W, Barnes DR et al (2017) Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 49:1113–1119. https://doi.org/10.1038/ng.3874

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Incalza MA, D’Oria R, Natalicchio A et al (2018) Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol 100:1–19

    CAS  Article  Google Scholar 

  25. Johnson JL, Abecasis GR (2017) GAS power calculator: web-based power calculator for genetic association studies. bioRxiv 164343

  26. Kathiresan S, Voight BF, Purcell S et al (2009) Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41:334–341. https://doi.org/10.1038/ng.327

    CAS  Article  PubMed  Google Scholar 

  27. Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL (2017) Oxidative stress in atherosclerosis. Curr Atheroscler Rep 19:1–11

    CAS  Article  Google Scholar 

  28. Khera AV, Kathiresan S (2017) Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 18:331–344

    CAS  Article  Google Scholar 

  29. Kinscherf R, Claus R, Wagner M et al (1998) Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J 12:461–467. https://doi.org/10.1096/fasebj.12.6.461

    CAS  Article  PubMed  Google Scholar 

  30. Konta A, Ozaki K, Sakata Y et al (2016) A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population. J Hum Genet 61:435–441. https://doi.org/10.1038/jhg.2015.171

    CAS  Article  PubMed  Google Scholar 

  31. Koyama S, Ito K, Terao C et al (2020) Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat Genet 52:1169–1177. https://doi.org/10.1038/s41588-020-0705-3

    CAS  Article  PubMed  Google Scholar 

  32. Lahiri DK (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 11:5444

    Article  Google Scholar 

  33. Moradi MT, Yari K, Rahimi Z et al (2015) Manganese superoxide dismutase (MnSOD Val-9Ala) gene polymorphism and susceptibility to gastric cancer. Asian Pacific J Cancer Prev 16:485–488. https://doi.org/10.7314/APJCP.2015.16.2.485

    Article  Google Scholar 

  34. Nikpay M, Goel A, Won HH et al (2015) A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 47:1121–1130. https://doi.org/10.1038/ng.3396

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. O’Donnell C, Kavousi M, Smith A et al (2011) Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Am Hear Assoc 124:2855

    Google Scholar 

  36. Ohashi M, Runge MS, Faraci FM, Heistad DD (2006) MnSOD deficiency increases endothelial dysfunction in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 26:2331–2336. https://doi.org/10.1161/01.ATV.0000238347.77590.c9

    CAS  Article  PubMed  Google Scholar 

  37. Patel RS, Su S, Neeland IJ et al (2010) The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease. Eur Heart J 31:3017–3023. https://doi.org/10.1093/eurheartj/ehq272

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Peng G, Lin M, Zhang K et al (2016) Hemoglobin A1c can identify more cardiovascular and metabolic risk profile in OGTT-negative Chinese population. Inter J Med Sci 10:1028

    Article  Google Scholar 

  39. Pérez-Hernández N, Vargas-Alarcón G, Posadas-Sánchez R et al (2016) PHACTR1 gene polymorphism is associated with increased risk of developing premature coronary artery disease in mexican population. Int J Environ Res Public Health 13:803. https://doi.org/10.3390/ijerph13080803

    CAS  Article  PubMed Central  Google Scholar 

  40. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516

    CAS  Article  Google Scholar 

  41. Rodríguez-Pérez JM, Blachman-Braun R, Pomerantz A et al (2016) Possible role of intronic polymorphisms in the PHACTR1 gene on the development of cardiovascular disease. Med Hypotheses 97:64–70. https://doi.org/10.1016/j.mehy.2016.10.012

    CAS  Article  PubMed  Google Scholar 

  42. Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A (2016) Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 4:256

    Article  Google Scholar 

  43. Souiden Y, Mallouli H, Meskhi S et al (2016) MnSOD and GPx1 polymorphism relationship with coronary heart disease risk and severity. Biol Res 49:22. https://doi.org/10.1186/s40659-016-0083-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Steffensen LB, Rasmussen LM (2018) A role for collagen type IV in cardiovascular disease? Am. J Physiol Hear Circ Physiol 315:H610–H625

    CAS  Article  Google Scholar 

  45. Sun X, Sun J, Zhao D et al (2019) Phosphatase and actin regulator 1 rs9349379 polymorphism is associated with an elevated susceptibility to coronary artery disease: a meta-analysis. J Gene Med 33:925–928. https://doi.org/10.1002/jgm.3110

    CAS  Article  Google Scholar 

  46. Szczygieł E, Słowik A (2013) Risk of myocardial infarction polymorphisms on chromosome 9P21.3 and the risk of ischaemic stroke-replication of the results obtained in GWAS. J Neurol Sci 333:e274. https://doi.org/10.1016/j.jns.2013.07.1045

    Article  Google Scholar 

  47. Szpakowicz A, Kiliszek M, Pepinski W et al (2015) The rs12526453 polymorphism in an intron of the PHACTR1 gene and its association with 5-year mortality of patients with myocardial infarction. PLoS ONE 10:e0129820. https://doi.org/10.1371/journal.pone.0129820

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Tajbakhsh A, Sadegh Khorrami M, Mahdi Hassanian S et al (2016) The 9p21 locus and its potential role in atherosclerosis susceptibility; molecular mechanisms and clinical implications. Curr Pharm Des 22:5730–5737

    CAS  Article  Google Scholar 

  49. Tian C, Liu T, Fang S et al (2012) Association of C47T polymorphism in SOD2 gene with coronary artery disease: a case-control study and a meta-analysis. Mol Biol Rep 39:5269–5276. https://doi.org/10.1007/s11033-011-1324-y

    CAS  Article  PubMed  Google Scholar 

  50. Toda N, Tanabe S, Nakanishi S (2011) Nitric oxide-mediated coronary flow regulation in patients with coronary artery disease: recent advances. Int J Angiol 20:121–134

    Article  Google Scholar 

  51. Van Der Harst P, Verweij N (2018) Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res 122:433–443. https://doi.org/10.1161/CIRCRESAHA.117.312086

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. van der Laan SW, Siemelink MA, Haitjema S et al (2018) Genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques. Circ Genomic Precis Med 11:e002115. https://doi.org/10.1161/CIRCGEN.118.002115

    CAS  Article  Google Scholar 

  53. Wakil SM, Ram R, Muiya NP et al (2016) A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs. Atherosclerosis 245:62–70. https://doi.org/10.1016/j.atherosclerosis.2015.11.019

    CAS  Article  PubMed  Google Scholar 

  54. Winsvold BS, Nelson CP, Malik R et al (2015) Genetic analysis for a shared biological basis between migraine and coronary artery disease. Neurol Genet 1:e10. https://doi.org/10.1212/NXG.0000000000000010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Zeller T, Seiffert M, Müller C et al (2017) Genome-wide association analysis for severity of coronary artery disease using the gensini scoring system. Front Cardiovasc Med 4:57. https://doi.org/10.3389/fcvm.2017.00057

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the study participants. In addition, the authors thank Dr. Mohammad Ali Mohammadi for technical guidance.

Funding

This study was supported by the research grant of Kerman University of Medical Sciences, Kerman, Iran (Grant No. 95000566).

Author information

Affiliations

Authors

Contributions

AY and KS designed the study. AY and FH performed the experiments and interpreted the data. AY and NSG were involved in revising the manuscript critically for important intellectual content. MRZ helped with statistical analysis and interpretation of data. KS supervised the research. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kolsoum Saeidi.

Ethics declarations

Conflict of Interest

The Authors declare that there is no conflict of interest.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 395 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yari, A., Saleh-Gohari, N., Mirzaee, M. et al. A Study of Associations Between rs9349379 (PHACTR1), rs2891168 (CDKN2B-AS), rs11838776 (COL4A2) and rs4880 (SOD2) Polymorphic Variants and Coronary Artery Disease in Iranian Population. Biochem Genet (2021). https://doi.org/10.1007/s10528-021-10089-0

Download citation

Keywords

  • Coronary artery disease
  • CAD severity
  • PHACTR1
  • CDKN2B-AS1
  • COL4A2
  • SOD2