Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy

Rajnikant Patel, Do Sun Lim, Deepa Reddy, Sherif F. Nagueh, Sylvia Lutucuta, Michael J. Sole, William A. Zoghbi, Miguel A. Quiñones, Robert Roberts, Ali J. Marian

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Abstract

Patients with hypertrophic cardiomyopathy (HCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity, which is partly due to the diversity of causal mutations, genetic background (modifier genes), and probably environmental factors. We determined association of functional variants of tumor necrosis factor (TNF)-α, interleukin-6 (IL6), insulin-like growth factor-2 (IGF2), transforming growth factor-β1 (TGFB1), and aldosterone synthase (CYP11B2) genes, all previously implicated in cardiac hypertrophy, with the severity of LVH in patients with HCM. TWo-dimensional echocardiography was performed and demographic variables were recorded in 142 genetically independent patients. Indices of LVH including interventricular septal thickness (IVST), left ventricular mass index (LVMI), and LVH score were measured/calculated. TNF-α - 308G/A, IL6 - 174G/C, IGF2 820G/A, TGFB1 - 509C/T, and CYP11B2 - 344T/C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were identified by the presence of specific electrophoretic patterns and their distributions were according to the Hardy-Weinberg equilibrium. Demographic variables were not significantly different among the genotypes. Subjects with the AA genotype of TNF-α (n = 8) were approximately 13 years younger at the time of clinical diagnosis. Despite a younger age, they had a greater mean LVMI than those with the GG (n=94) or GA (n=33) genotypes (191.8 ± 59.5 v 139.1 ± 47.3 v 132.1 ± 34.3, respectively, P = 0.004). TNF-α - 308G/A genotypes accounted for 6.0% of variability of LVMI (P=0.002). Mean IVST, LVEDD, and LVH score were not significantly different. Variants of IL6, IGF2, TGFB1, and CYP11B2 were not associated with indices of LVH. The uncommon allele of TNF-α -308G/A polymorphism, known to produce more TNF-α, was associated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicated in cardiac hypertrophy, were not associated with the indices of LVH. These results suggest that TNF-α is a modifier gene for HCM.

Original languageEnglish
Pages (from-to)2369-2377
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume32
Issue number12
DOIs
Publication statusPublished - 2000
Externally publishedYes

Keywords

  • Cytokines
  • Genes
  • Growth factors
  • Hypertrophy
  • Polymorphism

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Patel, R., Lim, D. S., Reddy, D., Nagueh, S. F., Lutucuta, S., Sole, M. J., Zoghbi, W. A., Quiñones, M. A., Roberts, R., & Marian, A. J. (2000). Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 32(12), 2369-2377. https://doi.org/10.1006/jmcc.2000.1267