Genetic variation in SCN10A influences cardiac conduction

Abstract

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10−15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10−5 to 10−20). SCN10A encodes NaV1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a−/− mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.

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Figure 1
Figure 2: Structure of the SCN10A locus on chromosome 3 among Indian Asians in the genome-wide association study and the 978 Europeans in the replication sample, genotyped with the Illumina 610 array.
Figure 3: PR interval and heart rate in conscious Scn10a−/− (n = 6) and wild-type (n = 4) mice recorded by telemetry.

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Acknowledgements

We thank the participants involved in the research. The LOLIPOP study was supported by the British Heart Foundation (SP/04/002) and by the Wellcome Trust (084723/Z/08/Z). Studies in the AGNES population were supported by the Netherlands Heart Foundation (Grant 2007B202) and the Leducq Foundation (Grant 05-CVD). J.Z. was supported by a BBSRC LOLA award (BB/F000227/1). R.K. was supported by the British Heart Foundation (Grant F/99089). M.N.W. is supported by the Biotechnology and Biological Sciences Research Council grant BB/F020481/1. W.M. is funded by the National Institute for Health Research Biomedical Research Centres scheme. J.N.W. is a member of the Wellcome Trust-funded London Pain Consortium. We thank G. Turner and M. Minett for maintaining the Scn10a-null mutant mouse colony, M.W. Tanck and R. Pazoki for help in statistical analyses and S. Rothery for technical assistance.

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Design and scientific rationale: J.C.C., J.Z., C.M.N.T., C.R.B., R.K., W.M., N.J.S., R.de.S., A.A.M.W., P.A., M.Y., J.S., P.E., J.N.W. and J.S.K. Obtained funding: J.C.C., C.M.N.T., C.R.B., R.K., N.J.S., A.A.M.W., P.A., M.Y., P.E., J.N.W. and J.S.K. Recruitment and characterization of participants: J.C.C., C.R.B., R.K., J.S.S., L.R.C.D., J.S.S.G.de.J., N.J.S., A.A.M.W., P.E. and J.S.K. Analyzed ECG readings: J.C.C., C.M.N.T., C.R.B., M.N., A.L., J.S.S., S.P., M.K.K., L.R.C.D., J.S.S.G.de.J. and A.A.M.W. Performed genotyping: J.C.C., C.R.B., W.Z., J.S.S., L.R.C.D., J.S.S.G.de.J., R.de.S., A.A.M.W., P.E. and J.S.K. PCR experiments: J.Z., C.M.N.T., R.K., U.S., I.E-H., N.J.S., J.C.C., J.N.W. and J.S.K. Mouse ECG studies: C.M.N.T., R.K., M.N., U.S., R.de.S., P.E., J.N.W., J.C.C. and J.S.K. Performed statistical analysis: J.C.C., C.M.N.T., C.R.B., W.Z., M.N., J.S.S., G.D., M.N.W., J.S.S.G.de.J., M.J.E.S., R.D.S., A.A.M.W., P.E. and J.S.K. Drafted manuscript: J.C.C., J.Z., C.M.N.T., J.S.S., R.de.S., J.S., P.E., J.N.W. and J.S.K. Critically revised manuscript: J.C.C., J.Z., C.M.N.T., C.R.B., W.Z., R.K., M.N., A.L., J.S.S., M.K.K., G.D., U.S., I.E-H., M.N.W., L.R.C.D., J.S.S.G.de.J., M.J.E.S., W.M., N.J.S., R.de.S., A.A.M.W., P.A., J.S., M.Y., P.E., J.N.W. and J.S.K.

Correspondence to John C Chambers or Jaspal S Kooner.

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Chambers, J., Zhao, J., Terracciano, C. et al. Genetic variation in SCN10A influences cardiac conduction. Nat Genet 42, 149–152 (2010) doi:10.1038/ng.516

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