Endothelin 1 gene as a modifier in dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a myocardial disease of unknown etiology with left ventricular dilatation and impaired myocardial contractility leading to heart failure. It is considered to be a multifactorial disorder with the interplay of both genetic and environmental factors. One of the possible genes implicated in DCM is endothelin 1 (EDN1). The genetic variants of EDN1 may be involved in the pathophysiology of DCM hence the entire EDN1 gene was screened to examine for the possible genotypic associations with DCM. A total of 115 DCM patients and 250 control subjects were included in the present study. PCR based SSCP analysis was carried out followed by commercial sequencing. Screening of EDN1 revealed two common and two rare polymorphisms. Allelic and genotypic frequencies were estimated in patient and control groups by appropriate statistical tests. The heterozygotes of insertion variation (+138A) were found to exhibit four-fold increase risk to DCM (OR=4.12, 95% CI 2.10-8.08; p=0.0001). The two rare variants (G>A transition (rs150035515) at c.90 and C>T transition (rs149399492) at c.119) observed in the present study were found to be unique in DCM. The secondary mRNA structures of these variations were found to have less free energy than wild type. The haplotype analysis revealed 4A-T to be risk haplotype for DCM (OR 5.90, 95% CI 2.29-15.25, p=0.0001). In conclusion, EDN1 polymorphisms (+138A, A30A, T40I) appear to play a significant role in the pathogenesis of DCM, as they influence the stability of protein. The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure.
['Matsa|Lova Satyanarayna|LS|', 'Sagurthi|Someswar Rao|SR|', 'Ananthapur|Venkateshwari|V|', 'Nalla|Swapna|S|', 'Nallari|Pratibha|P|']
D000293:Adolescent D000328:Adult D002311:Cardiomyopathy, Dilated D019332:Endothelin-1 D005091:Exons D005260:Female D056726:Genetic Association Studies D020022:Genetic Predisposition to Disease D014644:Genetic Variation D006239:Haplotypes D006801:Humans D008297:Male D008875:Middle Aged D016254:Mutagenesis, Insertional D010641:Phenotype D017354:Point Mutation D055550:Protein Stability D055815:Young Adult
Endothelin Dilated cardiomyopathy Hemodynamics Vasoconstriction