Letter by Hong et al Regarding Article, “Cardiac Sodium Channel (SCN5A) Variants Associated With Atrial Fibrillation”
To the Editor:
We read with great interest the excellent article by Dr Darbar and colleagues,1 in which the authors resequence the entire SCN5A coding region in 375 subjects with either lone atrial fibrillation (AF) or AF associated with heart disease. They draw a conclusion that mutations or rare variants in SCN5A may predispose patients with or without underlying heart disease to AF. However, although their findings represent a good starting point, it is insufficient to recommend that the vulnerability to AF is associated with disorders of the cardiac sodium channel on the basis of a single mutated gene detected by DNA analysis.
We would like to express 4 concerns. Firstly, it is possible that, apart from the SCN5A mutations, other mutations in the cardiac sodium channel–related genes may be related to the vulnerability to AF. The authors should have provided more information on the presence or absence of other mutations in genes, such as the Src family tyrosine kinase Fyn2 and fibroblast growth factor homologous factor 1B (FHF1B).3 Secondly, the SCN5A mutation is not the sole cause of the phenotype, so it should not be recommended for a large-scale risk assessment program. More studies on the molecular events that lead to the vulnerability to AF are needed to fully develop a panel of genetic tests to be used as prognostic and risk assessment tools. Thirdly, this study is based on participants living in the United States, so the results may not be applicable to Asians. Furthermore, the mutations or variants in SCN5A may be associated with epigenetic inheritance. Could the authors comment on the potential effect of racial diversity and inheritance on the presence of SCN5A mutations? Lastly, human evolution and changing environment will induce different gene mutations, which work as the initiating factors and set in motion a cascade of cellular events that regulate cellular function. With the development of human evolution and the environment, gene mutations are changing. Thus, the mutations in SCN5A may be the risk factors for the incidence of AF in patients during the research period but not for patients beyond the research period.
Source of Funding
The work of the authors is partially supported by grants from the National Science Foundation of China (30770958 and 30871141).
Darbar D, Kannankeril PJ, Donahue BS, Kucera G, Stubblefield T, Haines JL, George AL Jr, Roden DM. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008; 117: 1927–1935.
Ahern CA, Zhang JF, Wookalis MJ, Horn R. Modulation of the cardiac sodium channel NaV1.5 by Fyn, a Src family tyrosine kinase. Circ Res. 2005; 96: 991–998.
Liu CJ, Dib-Hajj SD, Renganathan M, Cummins TR, Waxman SG. Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B. J Biol Chem. 2003; 278: 1029–1036.