Genetic variation in SCN10A influences cardiac conduction

Chambers, John C.; Zhao, Jing; Terracciano, Cesare; Bezzina, Connie R.; Zhang, Weihua; Kaba, Riyaz A.; Navaratnarajah, Manoraj; Lotlikar, Amol; Sehmi, Joban; Kooner, Manraj K.; Deng, Guohong; Siedlecka, Urszula; Parasramka, Saurabh; El-Hamamsy, Ismaı̈l; Wass, Mark N.; Dekker, Lukas; Jong, Jonas S.S.G. de; Sternberg, Michael J.E.; McKenna, William J.; Severs, Nicholas J.; Silva, Ranil de; Wilde, Arthur A.M.; Anand, Praveen; Yacoub, Magdi H.; Scott, James A.; Elliott, Paul; Wood, John N.; Kooner, Jaspal S.

doi:10.1038/ng.516

Cited by 257 publications

(288 citation statements)

References 32 publications

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“…However, recently several genome-wide association studies have linked polymorphisms in SCN10A, the gene encoding Nav1.8, to prolongation of PR and QRS intervals. 14,15 Subsequently, Nav1.8 expression was demonstrated in mouse and human cardiac myocytes and intracardiac neurons. 16 In cardiac myocytes, block of Nav1.8 reduces late Na C current and shortens action potential duration, 17 while block of Nav1.8 in intracardiac neurons reduces action potential frequency.…”

Section: Sodium Channelsmentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype.

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Section: Sodium Channelsmentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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“…According to previous reports, 22,23) we defined cardiac conduction abnormalities as first-degree heart block, bundlebranch block, and bifascicular block. We extracted clinical data including the occurrence of these abnormalities from a review of the patients' medical records in 2003.…”

Section: Methodsmentioning

confidence: 99%

“…22) The SCN10A gene encodes the neuronal sodium channel isoform, Na V 1.8. Several recent genome-wide association studies (GWAS) [22][23][24][25][26] have linked SCN10A to the PR interval and QRS duration, strongly suggesting some role for Na V 1.8 in cardiac electrophysiology. The allele A of the SCN10A gene polymorphism (rs6795970) was associated with increased risk of first-degree heart block, bundle-branch block, and bifascicular heart block.…”

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confidence: 99%

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Association Between Genetic Variation in the <i>SCN10A</i> Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy

et al. 2015

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SummaryArrhythmias are associated with reduced quality of life and poor prognosis in patients with hypertrophic cardiomyopathy (HCM). Recent genome-wide association studies revealed that a nonsynonymous single nucleotide polymorphism, rs6795970, in the SCN10A gene was associated with the PR interval. We examined whether the PR prolonging allele (A allele) in the SCN10A gene may be associated with cardiac conduction abnormalities in HCM patients.We genotyped the polymorphism in 149 HCM patients. Conduction abnormalities were defined as first-degree heart block, bundle-branch block, and bifascicular heart block. Patients were divided into two groups: group A consisted of 122 patients (82%) without a conduction abnormality; and group B consisted of 27 patients (18%) with one or more cardiac conduction abnormalities. The frequency distribution of the SCN10A genotypes (G/G, G/A, and A/A) among the patients with HCM was 71%, 26%, and 3%, respectively. A cardiac conduction abnormality was documented in 9% with G/G and 40% with G/A or A/A. There was a significant difference in the genotype distribution between the two groups (P = 0.0002). In the dominant A allele model, there was a significant difference in genotypes between the two groups (P < 0.0001). In addition, the A allele remained significant after adjusting for other covariates in a multivariate model (odds ratio = 6.30 [95% confidence interval: 2.24 to 19.09], P = 0.0005).The rs6795970 in the SCN10A gene, which is reported to carry a high risk of heart block, might be associated with cardiac conduction abnormalities in HCM patients. (Int Heart J 2015; 56: 421-427)

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“…Sodium channel mutations in SCN5A result in cardiac conduction disease [10]. SCN10A has also been associated with conduction albeit in the atrioventricular node [11]. Repolarisation of the action potential is achieved by inactivation of L-type calcium currents and opening of a number of potassium channels.…”

Section: An Overview Of the Electrophysiology Of The Sanmentioning

confidence: 99%

Potassium channels in the sinoatrial node and their role in heart rate control

Aziz

Tinker

2018

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Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.

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Genetic variation in SCN10A influences cardiac conduction

Cited by 257 publications

References 32 publications

Cardiac ion channels

Cardiac ion channels

Association Between Genetic Variation in the <i>SCN10A</i> Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy

Potassium channels in the sinoatrial node and their role in heart rate control

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