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

Patients with hypertrophic cardiomyopathy (DCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality an d morbidity, which is partly due to the diversity of causal mutations, gene tic background (modifier genes), and probably environmental factors. We det ermined association of functional variants of tumor necrosis factor (TNF)-a lpha, interleulrin-6 (IL6), insulin-like growth factor-2 (IGF2), transformi ng growth factor-beta1 (TGFB1), and aldosterone synthase (CYP11B2) genes, a ll previously implicated in cardiac hypertrophy, with the severity of LVH i n patients with HCM. Two-dimensional echocardiography was performed and dem ographic variables were recorded in 142 genetically independent patients. I ndices of LVH including interventricular septal thickness (IVST), left Vent ricular mass index (LVMI), and LVH score were measured/calculated. TNF-alph a -308G/A, IL6 -174G/C, IGF2 820G/A, TGFB1 - 509C/T, and CYP11B2 - 344T/C g enotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotgpes were identified by the presence o f specific electrophoretic patterns and their distributions were according to the Hardy-Weinberg equilibrium. Demographic variables were not significa ntly different among the genotypes. Subjects with the AA genotype of TNF-al pha (n = 8) were approximately 13 years younger at the time of clinical dia gnosis. 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-alpha -308G/A genotypes acc ounted for 6.0% of variability of LVMI (P = 0.002). Mean IVST, LVEDD, and L VH score were not significantly different. Variants of IL6, IGF2, TGFB1, an d CYP11B2 were not associated with indices of LVH. The uncommon allele of T NF-alpha - 308G/A polymorphism, known to produce more TNF-alpha, was associ ated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicat ed in cardiac hypertrophy, were not associated with the indices of LVH. The se results suggest that TNF-alpha is a modifier gene for HCM. (C) 2000 Acad emic Press.