Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

Javad Jabbari; Morten S. Olesen; Lei Yuan; Jonas B. Nielsen; Bo Liang; Vincenzo Macri; Ingrid E. Christophersen; Nikolaj Nielsen; Ahmad Sajadieh; Patrick T. Ellinor; Morten Grunnet; Stig Haunsø; Anders G. Holst; Jesper H. Svendsen; Thomas Jespersen

doi:10.1161/circgenetics.113.000442

Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

Javad Jabbari, Morten S. Olesen, Lei Yuan, Jonas B. Nielsen, Bo Liang, Vincenzo Macri, Ingrid E. Christophersen, Nikolaj Nielsen, Ahmad Sajadieh, Patrick T. Ellinor, Morten Grunnet, Stig Haunsø, Anders G. Holst, Jesper H. Svendsen, Thomas Jespersen

50 Citationer (Scopus)

Abstract

Background - Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Na_v1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r²=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results - SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10^-5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions - The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.

Originalsprog	Engelsk
Tidsskrift	Circulation: Cardiovascular Genetics
Vol/bind	8
Udgave nummer	1
Sider (fra-til)	64-73
Antal sider	10
ISSN	1942-325X
DOI	https://doi.org/10.1161/circgenetics.113.000442
Status	Udgivet - 4 feb. 2015

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10.1161/circgenetics.113.000442

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Jabbari, J., Olesen, M. S., Yuan, L., Nielsen, J. B., Liang, B., Macri, V., Christophersen, I. E., Nielsen, N., Sajadieh, A., Ellinor, P. T., Grunnet, M., Haunsø, S., Holst, A. G., Svendsen, J. H., & Jespersen, T. (2015). Common and rare variants in SCN10A modulate the risk of atrial fibrillation. Circulation: Cardiovascular Genetics, 8(1), 64-73. https://doi.org/10.1161/circgenetics.113.000442

Jabbari, J, Olesen, MS, Yuan, L, Nielsen, JB, Liang, B, Macri, V, Christophersen, IE, Nielsen, N, Sajadieh, A, Ellinor, PT, Grunnet, M, Haunsø, S, Holst, AG, Svendsen, JH & Jespersen, T 2015, 'Common and rare variants in SCN10A modulate the risk of atrial fibrillation.', Circulation: Cardiovascular Genetics, bind 8, nr. 1, s. 64-73. https://doi.org/10.1161/circgenetics.113.000442

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title = "Common and rare variants in SCN10A modulate the risk of atrial fibrillation.",

abstract = "Background - Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results - SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10-5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions - The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.",

keywords = "SCN10A atrial fibrillation",

author = "Javad Jabbari and Olesen, {Morten S.} and Lei Yuan and Nielsen, {Jonas B.} and Bo Liang and Vincenzo Macri and Christophersen, {Ingrid E.} and Nikolaj Nielsen and Ahmad Sajadieh and Ellinor, {Patrick T.} and Morten Grunnet and Stig Hauns{\o} and Holst, {Anders G.} and Svendsen, {Jesper H.} and Thomas Jespersen",

year = "2015",

month = feb,

day = "4",

doi = "10.1161/circgenetics.113.000442",

language = "English",

volume = "8",

pages = "64--73",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

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TY - JOUR

T1 - Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

AU - Jabbari, Javad

AU - Olesen, Morten S.

AU - Yuan, Lei

AU - Nielsen, Jonas B.

AU - Liang, Bo

AU - Macri, Vincenzo

AU - Christophersen, Ingrid E.

AU - Nielsen, Nikolaj

AU - Sajadieh, Ahmad

AU - Ellinor, Patrick T.

AU - Grunnet, Morten

AU - Haunsø, Stig

AU - Holst, Anders G.

AU - Svendsen, Jesper H.

AU - Jespersen, Thomas

PY - 2015/2/4

Y1 - 2015/2/4

N2 - Background - Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results - SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10-5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions - The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.

AB - Background - Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results - SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10-5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions - The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.

KW - SCN10A atrial fibrillation

U2 - 10.1161/circgenetics.113.000442

DO - 10.1161/circgenetics.113.000442

M3 - Journal article

C2 - 25085921

SN - 1942-325X

VL - 8

SP - 64

EP - 73

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 1

ER -

Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

Abstract

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