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.
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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
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
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
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
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
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
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
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
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
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
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
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
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
Ford T, Corcoran D, Padmanabhan S (2020) Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur Heart J 41:3239–3252
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
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
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
Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606
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
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
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
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
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
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
Johnson JL, Abecasis GR (2017) GAS power calculator: web-based power calculator for genetic association studies. bioRxiv 164343
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
Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL (2017) Oxidative stress in atherosclerosis. Curr Atheroscler Rep 19:1–11
Khera AV, Kathiresan S (2017) Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 18:331–344
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
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
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
Lahiri DK (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 11:5444
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
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
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
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
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
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
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
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516
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
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
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
Steffensen LB, Rasmussen LM (2018) A role for collagen type IV in cardiovascular disease? Am. J Physiol Hear Circ Physiol 315:H610–H625
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
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
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
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
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
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
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
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
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
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
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
We are grateful to the study participants. In addition, the authors thank Dr. Mohammad Ali Mohammadi for technical guidance.
This study was supported by the research grant of Kerman University of Medical Sciences, Kerman, Iran (Grant No. 95000566).
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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
- Coronary artery disease
- CAD severity