International Journal of Genetics and Genomics
Volume 2, Issue 5, October 2014, Pages: 84-91
Received: Mar. 25, 2014;
Accepted: Apr. 18, 2014;
Published: Nov. 10, 2014
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Advithi Rangaraju, Department of Genetics, Osmania University, Jamia Osmania, Hyderabad, Andhra Pradesh
Satyanarayana Matsa.Lova, Department of Genetics, Osmania University, Jamia Osmania, Hyderabad, Andhra Pradesh
Narasimhan Calambur, Cardiologist, CARE Hospitals, Hyderabad, Andhra Pradesh
Pratibha Nallari, Department of Genetics, Osmania University, Jamia Osmania, Hyderabad, Andhra Pradesh
Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the myocardium with a variable clinical course. Mutations in 14 sarcomeric genes have been implicated resulting in phenotypic and genotypic heterogeneity. The phenotypic expression of HCM is not only determined by the sarcomeric gene mutations but the genetic predilection of an individual also account for the inter-individual variability and genes with such functional variants that affect phenotypic expression are referred to as Modifier genes. Hence genetic variants of Angiotensin converting enzyme (ACE-2), Tumor necrosis factor- alpha (TNF-α) and Heat shock protein -70 (HSP70) genes have been considered in the present study to understand their role as modifiers of HCM. The study was carried out by Genotyping of 100 HCM and 100 controls by Polymerase chain reaction based restriction fragment length polymorphism analysis. The present study revealed a significant association of the HSP70-1 and HSP70-2 polymorphisms while ACE-2 and TNF-α genes were found to be statistically insignificant. However patients with the rare/variant genotypes were observed to have stronger clinical manifestations and echocardiographic parameters. This was further confirmed by Linkage disquillibrium analysis wherein individuals with the haplotypes GCGC and GCGT seemed to have increased susceptibility to HCM. The MDR analysis revealed a synergistic interaction of TNF-α with ACE-2 and HSP70 polymorphisms indicating their modifying effect in the presence of other environmental factors. Hence the present study emphasized the role of ACE-2, TNF-α and HSP70 polymorphisms as modifiers of the phenotypic expression in conjunction with other sarcoemric mutations and single nucleotide variations.
Modifier Genes in Hypertrophic Cardiomyopathy Patients of South Indian Cohort, International Journal of Genetics and Genomics.
Vol. 2, No. 5,
2014, pp. 84-91.
Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA, 2002. 287: p.1308-1320,
Marian AJ. Modifier genes for hypertrophic cardiomyopathy. Current Opinion in Cardiology, 2002. 17: p. 242-252.
Ortlepp JR., et al. Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene. Heart, 2002. 87: p. 270–275.
Donoghue M, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation Research, 2000, 87: p.1-9.
Danilczyk U et al. A story of two ACEs. Journal of Molecular Medicine, 2003 81: p. 227-234
Wang SX, et al. Polymorphisms of angiotensinconverting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy. Chinese Medical Journal, 2008. 121: p. 27–31
Yokoyama T, et al. Tumor Necrosis Factor-α Provokes a Hypertrophic Growth Response in Adult Cardiac Myocytes. Circulation, 1997. 95: p. 1247-1252
Kapadia S, et al. Soluble TNF binding proteins modulate the negative inotropic properties of TNF-α in vitro. American Journal of Physiology, 1995. 268: p. 517–525
Bryant D, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-α. Circulation, 1998. 97: p. 1375–1381.
Bozkurt B, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. Circulation, 1998. 97: p. 1382–1391.
Alfonso S and Richiardi PM A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics, 1994. 39(2): p.150–154.
Wilson AG, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of National Academy of Sciences U S A, 1997. 94: p. 3195–3159.
Gething MJ and Sambrook J. Protein folding in the cell. Nature, 1992. 355: p. 33-45.
Lahiri D and Nurnberger J. A rapid non enzymatic method for preparation of HMW DNA from blood for RFLP studies. Nucleic acids Research, 1991. 19: p. 5444
Verjans GM et al. Polymorphism of tumor necrosis factor-alpha (TNF-a) at position- 308G/A in relation to ankylosing spondylitis. Clinical and Experimental Immunology, 1994. 97: p. 45–47.
Milner CM and Campbell RD. Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics, 1992. 36: p. 357–362.
Ritchie MD et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. American Journal of Human Genetics, 2001. 69(1): p. 138-147.
Parrillo JE, et al. A circulating myocardial depressant substance in humans with septic shock. Journal of Clinical Investigations, 1985. 76: p.1539–1553.
Michie HR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. New England Journal of Medicine, 1998. 318:p. 1481–1486.
Torre-Amione G, et al. Tumor necrosis factor-a and tumor necrosis factor receptors in the failing human heart. Circulation, 1996. 93: p. 704 –711.
Nozaki N, et al. Soluble tumor necrosis factor receptors are elevated in relation to severity of congestive heart failure. Japanese Circulation Journal, 1997.61: p. 657– 664.
Patel R, et al. Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. Journal of Molecular Cell, 2000. 32(12): p. 2369-2377
Zhu J, et al. Increased Serum Levels of Heat Shock Protein 70 Are Associated With Low Risk Of Coronary Artery Disease. Arteriosclerosis, Thrombosis and Vascular Biolology, 2003. 23: p. 1055-1059.
Yih-Ru Wu, et al. Analysis of heat-shock protein 70 gene polymorphisms and the risk of Parkinson’s disease. Human Genetics, 2004.114: p. 236–241.
Liu J, et al. Effects of polymorphisms of heat shock protein 70 gene on ischemic stroke, and interaction with smoking in China. Clinical Chimica Acta, 2007. 384: p. 64–68.
Kim J, et al. Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia. European Archives of Psychiatry Clinical Neuroscience, 2008. 258: p. 239–244.
Pociot F, et al. Polymorphic analysis of the human MHC-linked heat shock 70 (HSP70-2) and HSP70-hom genes in insulin-dependent diabetes mellitus (IDDM).Scandinavian Journal of Immunology, 1993.38: p.491
Nackley AG, et al. Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure. Science, 2006. 314: p. 1930–1933.
Kimchi-Sarfaty C, et al. A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity. Science, 1998. 315: p. 525–528.