Modifier Genes in Hypertrophic Cardiomyopathy Patients of South Indian Cohort

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.