Association of anteroseptal hypokinesia after myocardial infarction with LDLR variation: A cross-sectional case-control study

Abstract

Cholesterol-rich LDL (LDL-C) is a major atherogenic lipoprotein. Elevated content of LDL-C in serum is associated with the higher risk of atherosclerosis. The plasma LDL-C level is regulated by LDL receptor. The T allele of rs2228671 in LDLR may be associated with decreased LDL-C levels. We investigated the association of rs2228671 of LDLR with myocardial infarction (MI) in people from Fars province of Iran. In this study 248 cases with MI and 256 healthy blood donors were tested for their rs2228671 LDLR polymorphism by PCR-RFLP method. The CC genotype of the rs2228671 single nucleotide polymorphism tended to be more common in patients while TT showed a higher frequency in the control group. Patients with anteroseptal hypokinesia had a significantly higher frequency of the CC genotype compared with other patients (p= 0.04, OR 8.217 and 95% CI 0.4755 to 142). Also frequency of C allele was increased as compared with that of the T allele in patients with anetroseptal hypokinesia (p=0.05, OR 7.637 and 95% CI 0.4367 to 124.6). There was also a significant increase of CT genotype in patients with abnormal heart rate (p=0.014). A significantly higher frequency of the CC genotype in patients with anetroseptal hypokinesia and its decrease in patients with abnormal heart rate suggest a complex relationship between LDLR variants and complications of MI.

Keywords

• Low density lipoprotein receptor,polymorphism,single nucleotide,myocardial Infarction,hypokinesia

References

1. Boyette, L.C., Manna, B., 2019. Physiology, Myocardial Oxygen Demand, In: StatPearls. StatPearls Publishing StatPearls Publishing LLC., Treasure Island (FL).
2. Carluccio, E., Tommasi, S., Bentivoglio, M., Buccolieri, M., Prosciutti, L., Corea, L., 2000. Usefulness of the severity and extent of wall motion abnormalities as prognostic markers of an adverse outcome after a first myocardial infarction treated with thrombolytic therapy. Am J Cardiol 85, 411-415.
3. Ference, B.A., Ginsberg, H.N., Graham, I., Ray, K.K., Packard, C.J., Bruckert, E., Hegele, R.A., Krauss, R.M., Raal, F.J., Schunkert, H., Watts, G.F., Boren, J., Fazio, S., Horton, J.D., Masana, L., Nicholls, S.J., Nordestgaard, B.G., van de Sluis, B., Taskinen, M.R., Tokgozoglu, L., Landmesser, U., Laufs, U., Wiklund, O., Stock, J.K., Chapman, M.J., Catapano, A.L., 2017. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 38, 2459-2472.
4. Fleischmann, K.E., Lee, T.H., Come, P.C., Goldman, L., Cook, E.F., Caguoia, E., Johnson, P.A., Albano, M.P., Lee, R.T., 1997. Echocardiographic prediction of complications in patients with chest pain. Am J Cardiol 79, 292-298.
5. Gofman, J.W., Lindgren, F., 1950. The role of lipids and lipoproteins in atherosclerosis. Science 111, 166-171.
6. Hadaegh, F., Derakhshan, A., Zafari, N., Khalili, D., Mirbolouk, M., Saadat, N., Azizi, F., 2017. Pre-diabetes tsunami: incidence rates and risk factors of pre-diabetes and its different phenotypes over 9 years of follow-up. Diabet Med 34, 69-78.
7. Hadaegh, F., Hasheminia, M., Abdi, H., Khalili, D., Bozorgmanesh, M., Arshi, B., Azizi, F., 2015. Prehypertension Tsunami: A Decade Follow-Up of an Iranian Adult Population. PLoS One 10, e0139412.
8. Hadaegh, F., Hasheminia, M., Lotfaliany, M., Mohebi, R., Azizi, F., Tohidi, M., 2013. Incidence of metabolic syndrome over 9 years follow-up; the importance of sex differences in the role of insulin resistance and other risk factors. PLoS One 8, e76304.

9. Han, J., Moe, G.K., 1964. NONUNIFORM RECOVERY OF EXCITABILITY IN VENTRICULAR MUSCLE. Circ Res 14, 44-60.
10. Harvard. https://www.afro.who.int/health-topics/cardiovascular-diseases (accessed 25/01 2020).
11. Incalcaterra, E., Hoffmann, E., Averna, M.R., Caimi, G., 2004. Genetic risk factors in myocardial infarction at young age. Minerva Cardioangiol 52, 287-312.
12. Jahangiri-Noudeh, Y., Akbarpour, S., Lotfaliany, M., Zafari, N., Khalili, D., Tohidi, M., Mansournia, M.A., Azizi, F., Hadaegh, F., 2014. Trends in cardiovascular disease risk factors in people with and without diabetes mellitus: a Middle Eastern cohort study. PLoS One 9, e112639.
13. Jha, C.K., Mir, R., Khullar, N., Banu, S., Chahal, S.M.S., 2018. LDLR rs688 TT Genotype and T Allele Are Associated with Increased Susceptibility to Coronary Artery Disease-A Case-Control Study. J Cardiovasc Dev Dis 5.
14. Kheirandish, M., Asgari, S., Lotfaliany, M., Bozorgmanesh, M., Saadat, N., Tohidi, M., Azizi, F., Hadaegh, F., 2014. Secular trends in serum lipid levels of a Middle Eastern adult population; 10 years follow up in Tehran lipid and glucose study. Lipids Health Dis 13, 20.
15. Krenz, M., Korthuis, R.J., 2012. Moderate ethanol ingestion and cardiovascular protection: from epidemiologic associations to cellular mechanisms. J Mol Cell Cardiol 52, 93-104.
16. Kuo, C.S., Munakata, K., Reddy, C.P., Surawicz, B., 1983. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 67, 1356-1367.
17. Leigh, S., Futema, M., Whittall, R., Taylor-Beadling, A., Williams, M., den Dunnen, J.T., Humphries, S.E., 2017. The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. J Med Genet 54, 217-223.
18. Libby, P., 2006. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83, 456s-460s. Linsel-Nitschke, P., Gotz, A., Erdmann, J., Braenne, I., Braund, P., Hengstenberg, C., Stark, K., Fischer, M., Schreiber, S., El Mokhtari, N.E., Schaefer, A., Schrezenmeir, J., Rubin, D., Hinney, A., Reinehr, T., Roth, C., Ortlepp, J., Hanrath, P., Hall, A.S., Mangino, M., Lieb, W., Lamina, C., Heid, I.M., Doering, A., Gieger, C., Peters, A., Meitinger, T., Wichmann, H.E., Konig, I.R., Ziegler, A., Kronenberg, F., Samani, N.J., Schunkert, H., 2008. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study. PLoS One 3, e2986.
19. Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R.E., Zou, G.Y., Hutchings, K., Johnson, C.Y., Tait, V., Wiens, M., Golding, J., van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A., Birkett, N., 2009. STrengthening the REporting of Genetic Association Studies (STREGA)--an extension of the STROBE statement. Genet Epidemiol 33, 581-598.
20. Lotfaliany, M., Akbarpour, S., Mozafary, A., Boloukat, R.R., Azizi, F., Hadaegh, F., 2015. Hypertension phenotypes and incident cardiovascular disease and mortality events in a decade follow-up of a Middle East cohort. J Hypertens 33, 1153-1161.
21. Martinelli, N., Girelli, D., Lunghi, B., Pinotti, M., Marchetti, G., Malerba, G., Pignatti, P.F., Corrocher, R., Olivieri, O., Bernardi, F., 2010. Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood 116, 5688-5697.
22. Moghaddam, M.M., Mohebi, R., Hosseini, F., Lotfaliany, M., Azizi, F., Saadat, N., Hadaegh, F., 2014. Distribution of ideal cardiovascular health in a community-based cohort of Middle East population. Ann Saudi Med 34, 134-142.
23. Mohseni, J., Kazemi, T., Maleki, M.H., Beydokhti, H., 2017. A Systematic Review on the Prevalence of Acute Myocardial Infarction in Iran. Heart Views 18, 125-132.
24. Moran, A.E., Tzong, K.Y., Forouzanfar, M.H., Rothy, G.A., Mensah, G.A., Ezzati, M., Murray, C.J., Naghavi, M., 2014. Variations in ischemic heart disease burden by age, country, and income: the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob Heart 9, 91-99.
25. Motulsky, A.G., 1989. Genetic aspects of familial hypercholesterolemia and its diagnosis. Arteriosclerosis 9, I3-7.
26. Mulieri, L.A., Hasenfuss, G., Leavitt, B., Allen, P.D., Alpert, N.R., 1992. Altered myocardial force-frequency relation in human heart failure. Circulation 85, 1743-1750.
27. Nicolini, F., Fortuna, D., Contini, G.A., Pacini, D., Gabbieri, D., Zussa, C., De Palma, R., Vezzani, A., Gherli, T., 2017. The Impact of Age on Clinical Outcomes of Coronary Artery Bypass Grafting: Long-Term Results of a Real-World Registry. Biomed Res Int 2017, 9829487.
28. Opthof, T., Sutton, P., Coronel, R., Wright, S., Kallis, P., Taggart, P., 2012. The Association of Abnormal Ventricular Wall Motion and Increased Dispersion of Repolarization in Humans is Independent of the Presence of Myocardial Infarction. Front Physiol 3, 235.
29. Peels, K.H., Visser, C.A., Dambrink, J.H., Jaarsma, W., Wielenga, R.P., Kamp, O., Kingma, J.H., van Glist, W.H., 1996. Left ventricular wall motion score as an early predictor of left ventricular dilation and mortality after first anterior infarction treated with thrombolysis. The CATS Investigators Group. Am J Cardiol 77, 1149-1154.
30. Punzalan, F.E., Sy, R.G., Santos, R.S., Cutiongco, E.M., Gosiengfiao, S., Fadriguilan, E., George, P., Laurie, A., 2005. Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia. J Atheroscler Thromb 12, 276-283.
31. Rafieian-Kopaei, M., Setorki, M., Doudi, M., Baradaran, A., Nasri, H., 2014. Atherosclerosis: process, indicators, risk factors and new hopes. Int J Prev Med 5, 927-946.
32. Rose, G., 1964. FAMILIAL PATTERNS IN ISCHAEMIC HEART DISEASE. Br J Prev Soc Med 18, 75-80. Sandhu, M.S., Waterworth, D.M., Debenham, S.L., Wheeler, E., Papadakis, K., Zhao, J.H., Song, K., Yuan, X., Johnson, T., Ashford, S., Inouye, M., Luben, R., Sims, M., Hadley, D., McArdle, W., Barter, P., Kesaniemi, Y.A., Mahley, R.W., McPherson, R., Grundy, S.M., Bingham, S.A., Khaw, K.T., Loos, R.J., Waeber, G., Barroso, I., Strachan, D.P., Deloukas, P., Vollenweider, P., Wareham, N.J., Mooser, V., 2008. LDL-cholesterol concentrations: a genome-wide association study. Lancet 371, 483-491.
33. Soutar, A.K., 2001. LDL Receptor and Its Role in Inherited Disease. e LS.
34. Srivastava, R.A., Ito, H., Hess, M., Srivastava, N., Schonfeld, G., 1995. Regulation of low density lipoprotein receptor gene expression in HepG2 and Caco2 cells by palmitate, oleate, and 25-hydroxycholesterol. J Lipid Res 36, 1434-1446.
35. Stein, J.H., Neumann, A., Preston, L.M., Vandenberg, B.J., Parrillo, J.E., Calvin, J.E., Marcus, R.H., 1998. Improved risk stratification in unstable angina: identification of patients at low risk for in-hospital cardiac events by admission echocardiography. Clin Cardiol 21, 725-730.
36. Sudhof, T.C., Goldstein, J.L., Brown, M.S., Russell, D.W., 1985. The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228, 815-822.
37. van Zyl, T., Jerling, J.C., Conradie, K.R., Feskens, E.J., 2014. Common and rare single nucleotide polymorphisms in the LDLR gene are present in a black South African population and associate with low-density lipoprotein cholesterol levels. J Hum Genet 59, 88-94.
38. WHO. https://www.afro.who.int/health-topics/cardiovascular-diseases (accessed 25/01 2020).
39. Ye, H., Zhao, Q., Huang, Y., Wang, L., Liu, H., Wang, C., Dai, D., Xu, L., Ye, M., Duan, S., 2014. Meta-analysis of low density lipoprotein receptor (LDLR) rs2228671 polymorphism and coronary heart disease. Biomed Res Int 2014, 564940.
40. Zareba, W., Moss, A.J., 1995. Dispersion of repolarization. Relation to heart rate and repolarization duration. J Electrocardiol 28 Suppl, 202-206.
41. Zhang, L., Yuan, F., Liu, P., Fei, L., Huang, Y., Xu, L., Hao, L., Qiu, X., Le, Y., Yang, X., Xu, W., Huang, X., Ye, M., Zhou, J., Lian, J., Duan, S., 2013. Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: case-control study and meta-analysis. Clin Biochem 46, 727-732.
42. Zhu, H., Tucker, H.M., Grear, K.E., Simpson, J.F., Manning, A.K., Cupples, L.A., Estus, S., 2007. A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum Mol Genet 16, 1765-1772.