COMPLEX EVALUATION OF THE SIGNIFICANCE OF POPULATIONAL GENETIC MARKERS ASSOCIATED WITH MYOCARDIAL INFARCTION AND RISK FACTORS

Aim. To evaluate the utilization of complex significance evaluation in Russian population, of genetic markers of myocardial infarction identified in entire-genomic associative studies.

Material and methods. Group of MI patients (n=200) and control group (n=420) were created based on populational selection of 45-69 year old citizens of Novosibirsk (9400 persons), collected during the international project HAPIEE; myocardial infarction patients, admitted to intensive care unit of the Hospital № 1 (160 persons); sudden cardiac death victims, post forensic investigation (n=285). Longevity group was collected during home visits and in the nursing houses (n=85). Genomic DNA was extracted from venous blood and myocardial tissue by phenolchlorophorm method. Genes polymorphism was tested with PCR real-time according to the protocol by equipment developer (TaqMan, Applied Biosystems, USA), device ABI 7900HT. For the study, the following MNP were selected: rs499818, rs619203, rs10757278 and rs1333049 (chr. 9), rs1376251, rs2549513, rs4804611, rs17465637.

Results. Mononucleotide polymorphisms, that did not show differences at pretest stage, showed significant distinctions in the studied population. Two MNP were closely linked: rs10757278 and rs1333049 (chr. 9) so for further assessment the rs1333049 was retained. Among other seven, only five MNP showed relation with MI of various strength. Some, like the rs1333049 showed association with MI in all groups and subgroups, while the others — only in separate groups, with restriction by sex and gender. The rs2549513 and rs17465637 showed to be not associated with CHD at all, though rs2549513 showed association with lipid and glucose metabolism, as with the severity of coronary atherosclerosis and adverse prognosis for 1 year post-MI. The rs17465637 was just poorly associated with BMI.

Conclusion. Complex approach to assessment of polymorphism role is quite demanding, but provides with a high grade of insurance in the significance of the results obtained, of non-random character of the results, and makes it to choose the most credible, that have showed association not only with the main pathological phenotype, but with its risk factors.

1. Horne BD, Carlquist JF, Muhlestein JB, et al. Associations with myocardial infarction of six polymorphisms selected from a three-stage genome-wide association study. Am Heart J. 2007 Nov; 154 (5): 969-75.

2. Larson MG, Atwood LD, Benjamin EJ, et al. Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes. BMC Med Genet. 2007 Sep 19; 8 Suppl 1: S5.

3. Ozaki K, Tanaka T. Genome-wide association study to identify single-nucleotide polymorphisms conferring risk of myocardial infarction. Methods Mol Med. 2006; 128: 173-80.

4. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med., 2007, 2357, 443-53.

5. 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 Aug; 72 (8): 1213-7.

6. Schunkert H, Götz A, Braund P, et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation. 2008 Apr 1; 117 (13): 1675-84.

7. Shen GQ, Li L, Rao S, et al. Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler Thromb Vasc Biol. 2008 Feb; 28 (2): 360-5.

8. Lee CJ, Lee JY, Oum CY, et al. The Effect of FLT1 Variant on Long-Term Cardiovascular Outcomes: Validation of a Locus Identified in a Previous Genome-Wide Association Study. PLoS One. 2016 Oct 13; 11 (10).

9. MONICA Monograph and Multimedia Sourcebook. World’s largest study of heart disease, stroke, risk factors, and population trends 1979-2002. Edited by Hugh Tunstall-Pedoe (with 64 other contributors for the WHO MONICA Project) WHO, Geneva, 2003. 237 р.

10. Ivanova AA, Maksimov VN, Orlov PS, et al. Association of the genetic markers for myocardial infarction with sudden cardiac death. Indian Heart J. 2017 Apr; 69, Suppl 1: S8-S11.

11. Franceschini N, Carty C, Buzkova P, et al. Association of genetic variants and incident coronary heart disease in multi-ethnic cohorts. The PAGE Study. Circulation. 2011; 4: 661-72.

12. Bressler J, Folsom AR, Couper DJ, et al. Genetic variants identified in a European genomewide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study. Am J Epidemiol. 2010 Jan 1; 171 (1): 14-23.

13. Foroughmand AM, Nikkhah E, Galehdari H, Jadbabaee MH. Association study between coronary artery disease and rs1333049 and rs10757274 polymorphisms at 9p21 locus in South-West Iran. Cell J. 2015; 17: 89-98.

14. Jansen MD, Knudsen GP, Myhre R, et al. Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study. Mol Biol Rep. 2014; 41: 2733-43.

15. Ellis KL, Pilbrow AP, Frampton CM, et al. A Common Variant at Chromosome 9P21.3 Is Associated with Age of Onset of Coronary Disease but Not Subsequent Mortality. Circ Cardiovasc Genet. 2010; 3 (3): 286-93.

16. Buysschaert I, Carruthers KF, Dunbar DR, 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 (9): 1132-41.

17. Shesternya PA, Nikulina SYu, Shulman VA, et al. Clinical significance of coronary artery disease genetic markers: reality or far future? Russ J Cardiol, 2014; 10: 7-12. (In Russ.) Шестерня П.А., Шульман В.А., Никулина С.Ю., и др. Использование генетических маркеров ишемической болезни сердца в клинической практике: реальность или отдаленная перспектива? Российский кардиологический журнал, 2014; 10 (114): 7-12. DOI:10.15829/1560-4071-2014-10-7-12

18. Lozhkina NG, Maksimov VN, Kulikov IV, et al. Association of genetic markers with lowered retractive heart function at patients with acute coronary syndrome. Meditsina i obrazovaniye v Sibiri, 2013; 3. (In Russ.) Ложкина Н.Г., Максимов В.Н., Куликов И.В., и др. Ассоциация генетических маркеров со сниженной сократительной функцией сердца у больных с острым коронарным синдромом. Медицина и образование в Сибири: Электронный ресурс сетевое научное издание, 2013; 3. http://ngmu.ru/cozo/mos/article/text_full.php?id=1024

19. Kulikov IV, Lozhkina NG, Maksimov VN, et al. Genetic markers of severity of coronary vessels stenosis in patients with acute coronary syndrome. Sibirskiy nauchnyy meditsinskiy zhurnal, 2013; 33, 4: 65-70. (In Russ.) Куликов И.В., Ложкина Н.Г., Максимов В.Н., и др. Генетические маркеры тяжести поражения коронарных сосудов у больных с острым коронарным синдромом. Сибирский научный медицинский журнал, 2013; 33, 4: 65-70.

20. Shiffman D, Ellis SG, Rowland CM, et al. Identification of four gene variants associated with myocardial infarction. Am J Hum Genet. 2005; 77: 596-605.

21. Koch W, Hoppmann P, Schömig A, Kastrati A. Variations of specific non-candidate genes and risk of myocardial infarction: a replication study. Int J Cardiol. 2011; Feb 17, 147 (1): 38-41.

22. Martynova EA, Shesternya PA, Nikulina SYu. Association of polymorphisms of 6 chromosome with myocardial infarction. Sibirskoye meditsinskoye obozreniye, 2013; 2 (80): 24-7. (In Russ.) Мартынова Е.А., Шестерня П.А., Никулина С.Ю. Ассоциация полиморфизмов шестой хромосомы с развитием инфаркта миокарда. Сибирское медицинское обозрение, 2013; 2 (80): 24-7.

23. Yamada Y, Kato K, Oguri M, et al. Genetic risk for myocardial infarction determined by polymorphisms of candidate genes in a Japanese population. J Med Genet. 2008; Apr, 45 (4): 216-21.

24. Lozhkina NG, Maksimov VN, Orlov PS, et al. Genetic markers of negative outcomes of the acute coronary syndrome. Russ J Cardiol, 2014; 10: 19-22. (In Russ.) Ложкина Н.Г., Максимов В.Н., Орлов П. С., и др. Генетические маркеры неблагоприятных исходов острого коронарного синдрома. Российский кардиологический журнал, 2014; 10 (114): 19-22. DOI:10.15829/1560-4071-2014-10-19-22

25. Lozhkina NG, Maksimov VN, Ragino YuI, et al. Multifactor prediction of long-term outcomes of acute coronary syndrome with sustained ST segment elevation. Russ J Cardiol, 2015; 9: 25-31. (In Russ.) Ложкина Н.Г., Максимов В.Н., Рагино Ю.И., и др. Многофакторное прогнозирование отдаленных исходов острого коронарного синдрома со стойким подъемом сегмента ST. Российский кардиологический журнал, 2015; 9 (125): 25-31. DOI:10.15829/1560-4071-2015-9-25-31

26. He QC, Hu YY, Zhang QP, et al. A meta-analysis of three identified single nucleotide polymorphisms at 1p13.3 and 1q41 and their associations with lipid levels and coronary artery disease. Kaohsiung J Med Sci. 2017; Jan, 33 (1): 1-10.