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A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy.

ABSTRACT: AIMS:SCN5A is a disease-causing gene associated with familial dilated cardiomyopathy (FDC). We examined the possible association between a common polymorphism in the SCN5A gene (c.1673A>G-p.H558R; rs1805124) and the risk of dilated cardiomyopathy (DCM) occurrence. METHODS:We genotyped 185 DCM cases (familial DCM, idiopathic DCM and postischemic DCM) and 251 controls for the p.H558R polymorphism in the SCN5A gene, to test the association of the molecular epidemiology of the individuals with the presence/absence of various types of DCM. RESULTS:Our results showed that the rs1805124 polymorphism was significantly associated with DCM, and the association was more significant in patients with FDC; furthermore, in these individuals, the less frequent GG genotype was associated with a 7.39-fold increased risk of disease [95% confidence interval (95% CI) = 2.88-18.96; P?

SUBMITTER: Mazzaccara C

PROVIDER: S-EPMC6012048 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy.

Mazzaccara Cristina C Limongelli Giuseppe G Petretta Mario M Vastarella Rossella R Pacileo Giuseppe G Bonaduce Domenico D Salvatore Francesco F Frisso Giulia G

Journal of cardiovascular medicine (Hagerstown, Md.) 20180701 7

<h4>Aims</h4>SCN5A is a disease-causing gene associated with familial dilated cardiomyopathy (FDC). We examined the possible association between a common polymorphism in the SCN5A gene (c.1673A>G-p.H558R; rs1805124) and the risk of dilated cardiomyopathy (DCM) occurrence.<h4>Methods</h4>We genotyped 185 DCM cases (familial DCM, idiopathic DCM and postischemic DCM) and 251 controls for the p.H558R polymorphism in the SCN5A gene, to test the association of the molecular epidemiology of the individ ...[more]

PMID: 29782370

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Project description:Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University Aim To evaluate the Association of rs1042713 polymorphism of the ADRB2 gene with dilated idiopathic cardiomyopathy (DCMP) and myocardial dilation of ischemic origin (DMI). Subjects and methods The study included patients with ICMP and DMI in the number of 221 people. The average age of the subjects was in the range of 55.30 ± 9.69 years. We divided the patients into 2 groups: the first – patients diagnosed with idiopathic dilatation cardiomyopathy and the second-patients with myocardial dilatation of ichemic origin. The number of patients in the first group was 111, including 99 men (89.2%) and 12 women (10.8%). The average age of patients in this group is 51.73 ± 9.74 years, in men 51.00 ± 8.96 years, in women 57.75 ± 3.71 years. The second group included patients with myocardial dilatation of ischemic origin. Their number is 110 people, including 100 men (91.5%) and 10 women (8.5%). The average age of respondents is 58.68 ± 8.38 years, for men 58.29 ± 8.46 years, for women 62.90 ± 6.29 years. The control group included patients who had no manifestations of cardiovascular diseases. Their number is 121 people (average age 53.6 ± 4.8 years). The patients underwent laboratory and instrumental studies, as well as molecular and genetic studies of the 16 AG polymorphism of the ADRB2 gene (rs1042713). All patients underwent coronary angiography. Based on the anamnesis data and instrumental studies, those patients who could be said to have no risk factors for the development of dilatation of the heart cavities were identified in the first group. And those patients who were reliably diagnosed with CHD were in the second group, that is, dilatation of the heart cavities is due to a previous myocardial infarction, existing angina pectoris. Results In the group with DCMP 10.8% of patients were carriers of the common homozygous 16AA genotype, the heterozygous 16AG genotype-48.6%, and the rare homozygous 16GG genotype-40.5%. In the control group 11.8% of patients were identified as carriers of a homozygous genotype by a common allele, and 47.5% were carriers heterozygous genotype, and homozygous genotype for a rare allele – 40.7%. The analysis non revealed a statistically significant decrease in the frequency of carrying the homozygous 16GG genotype in patients with DCMP compared to the control group of the rs1042713 polymorphism of the ADRB2 gene. In the group with DM IG, there was no association with the rs1042713 polymorphism of the ADRB2 gene. Conclusion A statistically significant association of rs1042713 of the ADRB2 gene with DCMP was not found. The association of DMI c rs1042713 could not be confirmed.

Project description:Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.

Dataset Information

A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy.

Publications

A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy.

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