PREDICTIVE ROLE OF CHROMOSOME 9P21.3 POLYMORPHISMS AND THEIR ASSOCIATION WITH FAMILY HISTORY OF CORONARY HEART DISEASE IN PATIENTS WITH MYOCARDIAL INFARCTION

Aim. To investigate the association between single-nucleotide polymorphisms (SNPs) rs10757278 and rs1333049 of the 9p21.3 locus and family history of coronary heart disease (CHD) in myocardial infarction (MI) patients. Material and methods. The MI group (n=243) and the control group (n=280) were comparable by such parameters as age, gender, arterial hypertension, diabetes mellitus, hypercholesterolemia, overweight and obesity, abdominal obesity, and smoking history. However, the groups were significantly different in terms of family history of CHD (p=0,004). Genome DNA was extracted from venous blood using the phenol-chloroform extraction method. The SNPs rs10757278 (9p21.3) and rs1333049 (9Sр21.3) were tested using real-time polymerase chain reaction (PCR) and the AB 7900HT device, according to the producer’s protocol (TaqMan probes, Applied Biosystems, USA). Results. A statistically significant association between MI and the CC rs1333049 genotype or the GG rs10757278 genotype was observed in the whole study sample and separately in men and women. The MI odds ratio (OR) for carriers of the CC rs1333049 genotype was 2,02 (95% confidence interval, CI, 1,32–3,08) in the whole sample, 1,91 (1,11–2,95) in men, and 2,91 (1,22–6,91) in women. For carriers of the GG rs10757278 genotype, respective OR values were 1,98 (1,30– 3,02), 1,77 (1,08–2,87), and 2,94 (1,26–6,87). Among participants without CHD in family history, OR for the CC rs1333049 genotype (1,92, 95% CI 1,16–3,16) and the GG rs10757278 genotype (1,82, 95% CI 1,10–3,00) were comparable for those among MI patients with CHD in family history (respective OR 2,19 (1,28–3,75) and 2,23 (1,31–3,81)). Conclusion. For the first time in Russia, the association between MI-related polymorphisms of the 9p21.3 chromosome and family history of CHD was analysed. Two SNPs (rs1333049 and rs10757278) of the 9p21.3 locus predicted MI risk independently from either conventional risk factors or CHD in family history.

1. 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: 937–52.

2. Chow C. K., Islam S., Bautista L. et al. Parental history and myocardial infarction risk across the world: The INTERHEART study. J Am Coll Cardiol 2011; 57: 619–27.

3. Perk J., Backer G. D., Gohlke H. et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012, doi:10.1093.

4. Cardiovascular prevention. Russian recommendation. Cardiovascular therapy and prevention 2011; 10 (6) (Suppl.2) 64p. Russian (Кардиоваскулярная профилактика. Российские рекомендации ВНОК. Кардиоваскулярная терапия и профилактика. 2011; 10 (6). Приложение 2. 64 с.).

5. Motazacker M. M., Pirruccello J., Huijgen R. et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur Heart J 2012; 33 (11): 1360–6.

6. Van der Net J. B., Oosterveer D. M., Vermissen J. et al. Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia. Eur Heart J 2008; 29: 2195–201.

7. Maitra A., Dash D., John S. et al. A common variant in chromosome 9p21 associated with coronary artery disease in Asian Indians. J Genet 2010, 88: 113–8.

8. Hiura Y., Fukushima Y., Yuno M. et al. Validation of the association of genetic variants on chromosome 9p21 and 1q41 with myocardial infarction in a Japanese population. Circ J 2008, 72: 1213–7.

9. Shen G. Q., Rao S., Martinelli N. et al. Association between four SNP’s on chromosome 9p21 and myocardial infarction is replicated in an Italian population. J Hum Gen 2008, 53 (2): 144–150.

10. Franceschini N., Carty C., Buzkova P. et al. Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. Circ Cardiovasc Genet 2011, 4 (6): 661–72.

11. Maksimov V. N., Kulikov I. V., Orlov P. S. et al. Evaluation of association between 9 genetic polymorphisms and myocardial infarction in the Siberian population. Annals of the Russian Academy of Medical Sciences 2012, 5: 24–9. Russian (Максимов В. Н., Куликов И. В., Орлов П. С. и др. Проверка взаимосвязи между девятью однонуклеотидными полиморфизмами и инфарктом миокарда на сибирской популяции. Вестник РАМН 2012, 5: 24–9).

12. Smith J. G., Melander O., Lovkist H. et al. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ Cardiovasc Genet 2009, 2 (2): 159–64.

13. Helgadottir A., Thorleifsson G., Magnusson K. P. et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008, 40: 217–24.

14. Bown M. J., Braund P. S., Thompson J. et al. Association between the coronary artery disease risk locus on chromosome 9p21.3 and abdominal aortic aneurysm. Circ Cardiovasc Genet 2008, 1: 39–42.

15. Nazarenko M. S., Markov A. V., Sleptsov A. A. et al. The status of CDKN2A (P16INK4A и P14ARF) gene methylation in carotid arteries tissue in patient with atherosclerosis. Medical Genetic 2012, 11 (2): 34–7. Russian (Назаренко М. С., Марков А. В., Слепцов А. А. и др. Статус метилирования гена CDKN2A (P16INK4A и P14ARF) в тканях сонных артерий у больных атеросклерозом. Медицинская генетика 2012, 11 (2): 34–7).

16. Linsel-Nitschke P., Schunkert H. Chromosome 9p21 and coronary risk – the mystery continues. Atherosclerosis 2011, 214 (2): 257–58.

17. Musunuru K., Kathiresan S. Genetics of Coronary Artery Disease. Ann Rev Genomics Hum Genet 2010, 11: 5.1–5.18.

18. Broadbent H. M., Peden J. F., Lorkowski S. et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet 2008, 17: 806–14.

19. Ye S., Willeit J., Kronenberg F. et al. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol 2008, 52: 378–84.

20. Schunkert H., Erdmann J., Samani N. J. Genetics of myocardial infarction: a progress report. Eur. Heart J 2010, 31 (8): 918–25.

21. Buysschaert I., Carruthers K. F., Dunbar D. R. et al. A variant at chromosome 9p21 is associated with recurrent myocardial infarction and cardiac death after acute coronary syndrome: The GRACE Genetics Study. Eur. Heart J 2010, 31: 1132–41.

22. Scheffold T., Kullmann S., Huge A. et al. Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry. BMC Cardiovascular Disorders 2011, 11: 9. doi: 10.1186/1471–2261–11–9.