A common genetic variant within SCN10A modulates cardiac SCN5A expression
Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, Ivan P. Moskowitz
Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, Ivan P. Moskowitz
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Research Article

A common genetic variant within SCN10A modulates cardiac SCN5A expression

Abstract

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel–encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Authors

Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, Ivan P. Moskowitz

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Figure 4

SNP rs6801957 modulates EnhA activity.

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SNP rs6801957 modulates EnhA activity. Transient transgenic embryos at E...
Transient transgenic embryos at E14.5 harboring human 2.2-kb EnhA with major (A) and minor (B) allele of SNP rs6801957. Human EnhA with the major allele (n = 9) was sufficient to drive CCS expression (A), but human EnhA with the minor allele (n = 4) was not (B). (C) Correlation of SCN5A expression in human hearts with SNP rs6801957 genotype. SCN5A expression was assessed by RNA-seq in 42 human cardiac tissue samples, of which 19 were homozygous GG, 18 were heterozygous GA, and 6 were homozygous AA at locus rs6801957. Homozygous GG individuals had significantly higher SCN5A expression (428 ± 128 rpm) than GA (331 ± 104 rpm) or AA (322 ± 66 rpm) individuals. Each A allele reduced expression by 12% ± 6% (P = 0.01). A linear additive regression model was used to determine statistical significance. Lines within boxes represent median value; boxes represent interquartile range; whiskers represent 5th and 95th percentiles.