Korean Circ J.  2016 Sep;46(5):615-621. 10.4070/kcj.2016.46.5.615.

Association of rs10757274 and rs2383206 Polymorphisms on 9p21 locus with Coronary Artery Disease in Turkish Population

• Yayla C
• Okyay K
• Yılmaz A
• Åžahinarslan A
• Yar SaÄŸlam AS
• Eyiol A
• Bolayır H
• Sezenöz B
• MenevÅŸe S
• Çengel A

• KMID: 2389617
• DOI: http://doi.org/10.4070/kcj.2016.46.5.615

Abstract

BACKGROUND AND OBJECTIVES
Genetic predisposition is an important risk factor for coronary artery disease (CAD). In this study, we aimed to evaluate the impact of rs10757274 and rs2383206 polymorphisms in chromosome 9p21 on presence and severity of CAD in a Turkish population.
SUBJECTS AND METHODS
A total of 646 patients who underwent coronary angiography were included in this study. Coronary vessel score and Gensini score were calculated to assess the angiographic severity of CAD. Alleles of AA, AG, and GG were determined for rs10757274 (polymorphism-1) and rs2383206 (polymorphism-2) polymorphisms located in chromosome 9p21 from the blood samples.
RESULTS
There was a significant difference between the alleles in polymorphism-1 in the presence of coronary artery disease (38.9% in AA, 48.0% in GG and 56.4% in AG, p=0.017). However, there was no difference between the alleles in polymorphism-2. According to vessel scores, there was a significant difference between the alleles in polymorphism-1 (AA 0.71±1.04, GG 0.88±1.07, AG 1.06±1.12, p=0.018). In polymorphism-2, vessel scores did not show a difference between the alleles. In polymorphism-1, there was a significant difference in Gensini score (p=0.041). Gensini scores did not differ between the alleles in polymorphism-2 (p>0.05 for all). In multivariate analyses, none of the alleles was an independent factor for presence of CAD.
CONCLUSION
The presence of rs10757274 polymorphism including AG allele in chromosome 9p21 was related to CAD. However, this relationship was not independent of other cardiovascular risk factors.

Keyword

Genetics; Atherosclerosis; Polymorphism

MeSH Terms

Alleles
Atherosclerosis
Coronary Angiography
Coronary Artery Disease*
Coronary Vessels*
Genetic Predisposition to Disease
Genetics
Humans
Multivariate Analysis
Risk Factors

Figure

• 

  Fig. 1 Comparison of vessel scores between alleles in gene 1. Note that the vessel scores were 0.71±1.04 in AA, 0.88±1.07 in AG and 1.06±1.12 in GG allel (between three groups, p=0.018). Pairwise comparisons are presented.

Reference

1. Okrainec K, Banerjee DK, Eisenberg MJ. Coronary artery disease in the developing world. Am Heart J. 2004; 148:7–15.

2. Ahn SG, Yoon J, Kim J, et al. genotype- and phenotype-directed personalization of antiplatelet treatment in patients with non-ST elevation acute coronary syndromes undergoing coronary stenting. Korean Circ J. 2013; 43:541–549.

3. Shin DJ, Lee SH, Park S, Jang Y. Association between serine/threonine kinase 39 gene polymorphism, hypertension, and other cardiovascular risk factors in Koreans. Korean Circ J. 2013; 43:13–22.

4. Yoo SY, Kim J, Cheong S, et al. Rho-associated kinase 2 polymorphism in patients with vasospastic angina. Korean Circ J. 2012; 42:406–413.

5. Chan L, Boerwinkle E. Gene-environment interactions and gene therapy in atherosclerosis. Cardiol Rev. 1994; 2:130–137.

6. Roberts R, Stewart AF. Genes and coronary artery disease: where are we? J Am Coll Cardiol. 2012; 60:1715–1721.

7. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007; 316:1488–1491.

8. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007; 316:1491–1493.

9. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447:661–678.

10. Ding H, Xu Y, Wang X, et al. 9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population. Circ Cardiovasc Genet. 2009; 2:338–346.

11. Hinohara K, Nakajima T, Takahashi M, et al. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. J Hum Genet. 2008; 53:357–359.

12. Saleheen D, Alexander M, Rasheed A, et al. Association of the 9p21.3 locus with risk of first-ever myocardial infarction in Pakistanis: case-control study in South Asia and updated meta-analysis of Europeans. Arterioscler Thromb Vasc Biol. 2010; 30:1467–1473.

13. Kumar J, Yumnam S, Basu T, et al. Association of polymorphisms in 9p21 region with CAD in North Indian population: replication of SNPs identified through GWAS. Clin Genet. 2011; 79:588–593.

14. Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010; 303:648–656.

15. Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008; 40:217–224.

16. Emanuele E, Lista S, Ghidoni R, et al. Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease. Neurobiol Aging. 2011; 32:1231–1235.

17. Kral BG, Mathias RA, Suktitipat B, et al. A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry. J Hum Genet. 2011; 56:224–229.

18. Munir MS, Wang Z, Alahdab F, et al. The association of 9p21-3 locus with coronary atherosclerosis: a systematic review and meta-analysis. BMC Med Genet. 2014; 15:66.

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

20. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364:937–952.

21. Di Chiara A, Vanuzzo D. Does surveillance impact on cardiovascular prevention? Eur Heart J. 2009; 30:1027–1029.

22. CARDIoGRAMplusC4D Consortium. Deloukas P, Kanoni S, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013; 45:25–33.

23. Franceschini N, Carty C, Bůzková P, et al. Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. Circ Cardiovasc Genet. 2011; 4:661–672.

24. Dandona S, Stewart AF, Chen L, et al. Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol. 2010; 56:479–486.

25. Congrains A, Kamide K, Oguro R, et al. Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis. 2012; 220:449–455.

26. Yap KL, Li S, Muñoz-Cabello AM, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010; 38:662–674.

27. Vijayachandra K, Higgins W, Lee J, Glick A. Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog. 2009; 48:181–186.

28. Chen HH, Almontashiri NA, Antoine D, Stewart AF. Functional genomics of the 9p21.3 locus for atherosclerosis: clarity or confusion? Curr Cardiol Rep. 2014; 16:502.

29. Çakmak HA, Bayoğlu B, Durmaz E, et al. Evaluation of association between common genetic variants on chromosome 9p21 and coronary artery disease in Turkish population. Anatol J Cardiol. 2015; 15:196–203.

30. Onat A, Uğur M, Ciçek G, et al. The Turkish Adult Risk Factor survey 2009: similar cardiovascular mortality in rural and urban areas. Turk Kardiyol Dern Ars. 2010; 38:159–163.