A common polymorphism in SCN5A gene is associated with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation and impaired systolic function, which may proceed into congestive heart failure. Although DCM is a final common pathway of various acquired diseases, up to 50% of cases are reported to be idiopathic (i.e., without any obvious aetiological trigger) and approximately 20% of DCM cases display familial prevalence. More than 20 genes are associated with DCM in humans, although DCM genetic tests present low diagnostic sensibility (< 20%). DCM associated genes encode structural proteins of cardiomyocytes and ion channels. These last include SCN5A, which encodes the alpha subunit of the major Na+ channel in the heart, Nav1.5. Dilated cardiomyopathy with SCN5A mutations has been generally associated with reduced expression of the cardiac sodium channel Nav1.5. We hypothesized that the p.H558R polymorphism could be a genetic risk factor in dilated cardiomyopathy, as the R minor allele of this polymorphism has been shown to alter SCN5A function, by reducing depolarizing sodium current and modulating the biological effects of concomitant SCN5A mutations. We recruited 134 DCM patients (50 with familial DCM -FDCM-, 58 with idiopatic DCM and 26 patients affected by post-ischemic DCM) and 168 age, ethnicity, and gender matched controls. The mean age at diagnosis was 45+12 y., with a mean follow-up of 8.2+5.5 y. SCN5A was subject to comprehensive mutation scanning in all cases and to targeted genotyping of a common loss-of-function p.H558R polymorphism in controls. The Hardy-Weinberg law was applied to analyze distribution of SCN5A p.H558R genotypes. Association between the three genotypes and categorical variables were tested using the χ2 test or Fisher’s exact test. Mutation scanning of all SCN5A translated exons in 134 DCM patients reveals one novel mutation (c.A1383T, p.M463L) in a patient with idiopatic DCM. This mutation was absent in 350 unrelated chromosomes from matched healthy control and it produced a change in a highly conserved residue among species and isoforms. The major finding of this study was a significant difference in frequencies of the three p.H558R genotypes in familial DCM compared to normal controls: HH 40 vs 49%, HR 36 vs 44%, RR 24 vs 7%; p = 0.004). 60% of familial DCM subjects had at least one R allele compared with 51% of controls. The minor R allele frequency was 42% in familial DCM compared with 29% in the normal controls. Notably, compared with the HH and HR genotype, the RR genotype confers an OR for developing DCM in familial cases of 4.1 (95% CI 1.7-9.9; p = 0.001). Six FDCM patients carrying RR genotype (50%) experienced serious arrhythmic events; unlike in the remaining FDCM the percentage of patients who developed arrhythmic events was 29%. In conclusion, our data demonstrate that: (1) mutations in coding regions of SCN5A are not a common cause for DCM; (2) the SCN5A p.558RR genotype is associated with dilated cardiomyopathy in patients with familial DCM. This result may help to early identify candidates to develop DCM among asymptomatic relatives of FDCM patients in families without an identified mutation.