Response to Letter Regarding Article, “Cardiac Sodium Channel (SCN5A) Variants Associated with Atrial Fibrillation”
We welcome the salient comments by Hong and colleagues pertaining to our work on cardiac sodium channel variants associated with atrial fibrillation (AF).1 We agree that besides mutations in the α-subunit of SCN5A, variants in cardiac sodium channel–related genes may also increase the risk of developing AF. Indeed, our group has recently shown that mutations in the sodium channel β-subunits are also associated with AF.2 Furthermore, recent work implicates ion channels as participants in macromolecular signaling complexes regulating myocyte differentiation through coupling with downstream intracellular partners or even through direct transcriptional effects.3 Although the mechanisms whereby some SCN5A mutations produce AF and others generate ventricular phenotypes remains to be determined, one possible explanation for the phenotypic variability in sodium channel–linked diseases may be related to chamber- or disease-specific interactions between the channel and its partners. For this reason, cardiac sodium channel–related genes such as Src family tyrosine kinase Fyn and fibroblast growth factor homologous factor 1B are obvious candidate genes for AF.
Despite reports of potassium channel mutations in AF, extensive screening of AF cohorts has revealed that such mutations rarely cause the arrhythmia.4 In contrast, we showed that nearly 6% of AF probands carry heterozygous mutations or rare variants in SCN5A. Thus, cardiac sodium channel variants may increase the risk of developing AF in a very large number of people with AF. Once the common variants that predispose to AF have been identified, it may be possible to formulate and validate an AF risk score. Such a risk score would incorporate not only clinical predictors of AF but also gene variants that increase the risk of developing the disease.
Because our AF cohort consists largely of Americans of European or African descent, the generalizability of our results to other races and ethnicities is uncertain. Although not mentioned in the article, we did resequence SCN5A in a cohort of anonymous population controls obtained from the Coriell repository, representing 4 different ethnic groups (white, black, Hispanic, and Asian; n =47 for each group). The novel and previously reported rare coding region variants identified in our AF cohort were not identified in the Coriell samples, strongly suggesting that these variants are likely to be disease-causing even in an Asian population. Finally, we agree that the SCN5A variants identified in our AF cohort are likely responsible for incident AF and may not necessarily predispose to prevalent AF.
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.
Watanabe H, Darbar D, Ingram CR, Jiramongkolchai K, Chopra S, Kucera G, Stubblefield T. Loss of function mutations in sodium channel beta subunits associated with atrial fibrillation and ST-segment elevation. Circulation. 2007; 116 (suppl): II-54. Abstract.