GWAS Analysis of Sudden Cardiac Death Cases in a Turkish Population

Abstract

Objective: Sudden death is defined as death occurring within one hour of the onset of symptoms, with cardiovascular diseases being one of the leading causes. The most common genetic factors leading to sudden cardiac death are hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. In some cases, autopsies may reveal no evidence of long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or Brugada Syndrome. Materials and Methods: We collected samples from sudden cardiac death cases aged 5–40 years (arrhythmia as Group 1, hypertrophy as Group 2, and ischemic heart disease as Group 3) , as well as from healthy athletes (control group as Group 4), and analyzed them using genomewide association study (GWAS) with a DNA microchip containing 196,725 single nucleotide polymorphism (SNP) markers thought to be associated with sudden cardiac death or other cardiovascular diseases. Results: We detected any possible genetic variations or patterns that could elucidate the mechanisms underlying sudden cardiac death in a Turkish population. In our study group, two polymorphisms; rs2971851 and rs9609516, stood out as prominent variants compared with healthy elite athletes. Conclusion: We aimed to identify potential genetic variations or patterns that could shed light on the mechanisms underlying sudden cardiac death in the Turkish population. In our study group, two polymorphisms, rs2971851 and rs9609516, emerged as prominent variants when compared to healthy athletes.

Keywords

• Sudden cardiac death
• Microarray analysis
• GWAS
• Genetics
• Forensic medicine

References

1. 1. Markwerth P, Bajanowski T, Tzimas İ, DettmeYer R. Sudden cardiac death-update. İnt J Legal Med 2021 ;135(2): 483-95. google scholar
2. 2. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017; 135(10): e146-e603. google scholar
3. 3. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primarY arrhYthmia sYndromes: document endorsed bY HRS, EHRA, and APHRS in MaY 2013 and bY ACCF, AHA, PACES, and AEPC in June 2013. Heart RhYthm 2013; 10(12): 1932-63. google scholar
4. 4. Eckart RE, Shry EA, Burke AP, McNear JA, Appel DA, Castillo-Rojas LM, et al. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011; 58(12): 1254-61. google scholar
5. 5. Bush WS, Moore JH. Chapter 11: Genome-wide association studies. PLoS Comput Biol 2012; 8(12): e1002822. google scholar
6. 6. Ndiaye NC, Azimi Nehzad M, El Shamieh S, Stathopoulou MG, Visvikis-Siest S. Cardiovascular diseases and genome-wide association studies. Clin Chim Açta 2011; 412(19-20): 1697-701. google scholar
7. 7. Roshyara NR, Kirsten H, Horn K, Ahnert P, Scholz M. İmpact of pre-imputation SNP-filtering on genotype imputation results. BMC Genet 2014; 15: 88. google scholar
8. 8. Butters A, Arnott C, Sweeting J, Winkel BG, Semsarian C, İngles J. Sex disparities in sudden cardiac death. Circ ArrhYthm ElectrophYsiol 2021; 14(8): e009834. google scholar

9. 9. Matoba R, Shikata İ, İwai K, Onishi S, Fujitani N, Yoshida K, et al. An epidemiologic and histopathological studY of sudden cardiac death in Osaka Medical Examiner's Office. Jpn Circ J 1989; 53(12): 1581-8. google scholar
10. 10. Burger NB, Bekker MN, de Groot CJ, Christoffels VM, Haak MC. WhY increased nuchal translucencY is associated with congenital heart disease: a sYstematic review on genetic mechanisms. Prenat Diagn 2015; 35(6): 517-28. google scholar
11. 11. Lu X, Wang L, Lin X, Huang J, Charles Gu C, He M, et al. Genome-wide association studY in Chinese identifies novel loci for blood pressure and hYpertension. Hum Mol Genet 2015; 24(3): 865-74. google scholar
12. 12. Guo DC, Grove ML, Prakash SK, Eriksson P, Hostetler EM, LeMaire SA, et al. Genetic variants in LRP1 and ULK4 are associated with acute aortic dissections. Am J Hum Genet 2016; 99(3): 762-9. google scholar
13. 13. Kaludercic N, Scorrano L. MCUB hearts mitochondria in sickness, less in health. Circulation 2019; 140(21): 1734-6. google scholar
14. 14. Perera RK, Fischer TH, Wagner M, Dewenter M, Vettel C, Bork Nİ, et al. Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase tYpe 4. Sci Rep 2017; 7(1): 15222. google scholar
15. 15. Mika D, Bobin P, Lindner M, Boet A, Hodzic A, Lefebvre F, et al. SYnergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model. J Mol Cell Cardiol 2019; 133: 57-66. google scholar
16. 16. Wang Y, Chu C, Ren J, Mu JJ, Wang D, Liu FQ, et al. Genetic variants in renalase and blood pressure responses to dietarY salt and potassium interventions: a family-based association study. Kidney Blood Press Res 2014; 39(5): 497-506. google scholar
17. 17. Buraczynska M, Gwiazda-Tyndel K, Drop B, Zaluska W. Renalase gene Glu37Asp polYmorphism affects susceptibilitY to diabetic retinopathY in tYpe 2 diabetes mellitus. Açta Diabetol 2021; 58(12): 1595-602. google scholar
18. 18. Parmacek MS. Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation. Circ Res 2007; 100(5): 633-44. google scholar
19. 19. Baldwin TA, Dessauer CW. Function of AdenYlYl cYclase in heart: the AKAP connection. J Cardiovasc Dev Dis 2018; 5(1): 2. google scholar
20. 20. Marin W. A-kinase anchoring protein 1 (AKAP1) and its role in some cardiovascular diseases. J Mol Cell Cardiol 2020; 138: 99-109. google scholar
21. 21. Baroni MG, D'Andrea MP, Montali A, Pannitteri G, Barillâ F, Campagna F, et al. A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 1999; 19(12): 2975-80. google scholar
22. 22. Bacci S, Prudente S, Copetti M, Spoto B, Rizza S, Baratta R, et al. Joint effect of insulin signaling genes on cardiovascular events and on whole bodY and endothelial insulin resistance. Atherosclerosis 2013; 226(1): 140-5. google scholar
23. 23. Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B, Hart J, et al. ClinVar: improvements to accessing data. Nucleic Acids Res 2020; 48(D1): D835-D44. google scholar
24. 24. Wang J, Dron JS, Ban MR, Robinson JF, McİntYre AD, Alazzam M, et al. PolYgenic versus monogenic causes of hYpercholesterolemia ascertained clinicallY. Arterioscler Thromb Vasc Biol 2016; 36(12): 2439-45. google scholar
25. 25. Kokame K, Matsumoto M, Soejima K, Yagi H, İshizashi H, Funato M, et al. Mutations and common polYmorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A 2002; 99(18): 11902-7. google scholar
26. 26. AkiYama M, NakaYama D, Takeda S, Kokame K, Takagi J, MiYata T. CrYstal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. J Thromb Haemost 2013; 11(7): 1399-406. google scholar
27. 27. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G-> A (C282Y) HFE hereditarY haemochromatosis mutation in the USA. Lancet 2002; 359(9302): 211-8. google scholar
28. 28. Ellervik C, Tybjaerg-Hansen A, Appleyard M, Sillesen H, Boysen G, Nordestgaard BG. HereditarY hemochromatosis genotYpes and risk of ischemic stroke. Neurology 2007; 68(13): 1025-31. google scholar
29. 29. Yönal O, Hatirnaz O, AkYüz F, Köroğlu G, Ozbek U, Cefle K, et al. Definition of C282Y mutation in a hereditarY hemochromatosis familY from TurkeY. Turk J Gastroenterol 2007; 18(1): 53-7. google scholar
30. 30. van Gammeren A, de Baar E, Schrauwen L, van Wijngaarden P. Compound heterozYgous C282Y/Q283P and Q283P/H63D mutations in haemochromatosis. Br J Haematol 2015; 171(4): 650-1. google scholar
31. 31. Davis TM, BeilbY J, Davis WA, OlYnYk JK, JeffreY GP, Rossi E, et al. Prevalence, characteristics, and prognostic significance of HFE gene mutations in tYpe 2 diabetes: the Fremantle Diabetes Study. Diabetes Çare 2008; 31(9): 1795-801. google scholar
32. 32. Oliva R, Novials A, Sânchez M, Villa M, Ingelmo M, Recasens M, et al. The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2. Endocrine 2004; 24(2): 111-4. google scholar
33. 33. Yang Q, Wu F, Mi Y, Wang F, Cai K, Yang X, et al. Aberrant expression of miR-29b-3p influences heart development and cardiomyocyte proliferation by targeting NOTCH2. Cell Prolif 2020; 53(3): e12764. google scholar