A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation

Robert C. Wirka, Shamone Gore, David R Van Wagoner, Dan Arking, Steven A. Lubitz, Kathryn L. Lunetta, Emelia J. Benjamin, Alvaro Alonso, Patrick T. Ellinor, John Barnard, Mina K. Chung, Jonathan D. Smith

Research output: Contribution to journalArticle

Abstract

Background-A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown. Methods and Results-Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, >44G3A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P=0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P=0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (>60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P

Original languageEnglish (US)
Pages (from-to)87-93
Number of pages7
JournalCirculation: Arrhythmia and Electrophysiology
Volume4
Issue number1
DOIs
StatePublished - Feb 2011

Fingerprint

Atrial Fibrillation
Single Nucleotide Polymorphism
Genes
Allelic Imbalance
connexin 40
Messenger RNA
TATA Box
Population Control
Luciferases
Cardiac Myocytes
Alleles
Odds Ratio
Phenotype

Keywords

  • Allelic expression imbalance
  • Atrial fibrillation
  • Genetics
  • Ion channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Medicine(all)

Cite this

A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. / Wirka, Robert C.; Gore, Shamone; Wagoner, David R Van; Arking, Dan; Lubitz, Steven A.; Lunetta, Kathryn L.; Benjamin, Emelia J.; Alonso, Alvaro; Ellinor, Patrick T.; Barnard, John; Chung, Mina K.; Smith, Jonathan D.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 4, No. 1, 02.2011, p. 87-93.

Research output: Contribution to journalArticle

Wirka, RC, Gore, S, Wagoner, DRV, Arking, D, Lubitz, SA, Lunetta, KL, Benjamin, EJ, Alonso, A, Ellinor, PT, Barnard, J, Chung, MK & Smith, JD 2011, 'A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation', Circulation: Arrhythmia and Electrophysiology, vol. 4, no. 1, pp. 87-93. https://doi.org/10.1161/CIRCEP.110.959726
Wirka, Robert C. ; Gore, Shamone ; Wagoner, David R Van ; Arking, Dan ; Lubitz, Steven A. ; Lunetta, Kathryn L. ; Benjamin, Emelia J. ; Alonso, Alvaro ; Ellinor, Patrick T. ; Barnard, John ; Chung, Mina K. ; Smith, Jonathan D. / A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. In: Circulation: Arrhythmia and Electrophysiology. 2011 ; Vol. 4, No. 1. pp. 87-93.
@article{775ccf59d8aa4e5fb7cb8538b4884524,
title = "A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation",
abstract = "Background-A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown. Methods and Results-Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, >44G3A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P=0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P=0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (>60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P",
keywords = "Allelic expression imbalance, Atrial fibrillation, Genetics, Ion channels",
author = "Wirka, {Robert C.} and Shamone Gore and Wagoner, {David R Van} and Dan Arking and Lubitz, {Steven A.} and Lunetta, {Kathryn L.} and Benjamin, {Emelia J.} and Alvaro Alonso and Ellinor, {Patrick T.} and John Barnard and Chung, {Mina K.} and Smith, {Jonathan D.}",
year = "2011",
month = "2",
doi = "10.1161/CIRCEP.110.959726",
language = "English (US)",
volume = "4",
pages = "87--93",
journal = "Circulation: Arrhythmia and Electrophysiology",
issn = "1941-3149",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation

AU - Wirka, Robert C.

AU - Gore, Shamone

AU - Wagoner, David R Van

AU - Arking, Dan

AU - Lubitz, Steven A.

AU - Lunetta, Kathryn L.

AU - Benjamin, Emelia J.

AU - Alonso, Alvaro

AU - Ellinor, Patrick T.

AU - Barnard, John

AU - Chung, Mina K.

AU - Smith, Jonathan D.

PY - 2011/2

Y1 - 2011/2

N2 - Background-A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown. Methods and Results-Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, >44G3A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P=0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P=0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (>60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P

AB - Background-A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown. Methods and Results-Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, >44G3A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P=0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P=0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (>60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P

KW - Allelic expression imbalance

KW - Atrial fibrillation

KW - Genetics

KW - Ion channels

UR - http://www.scopus.com/inward/record.url?scp=79953767585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953767585&partnerID=8YFLogxK

U2 - 10.1161/CIRCEP.110.959726

DO - 10.1161/CIRCEP.110.959726

M3 - Article

C2 - 21076161

AN - SCOPUS:79953767585

VL - 4

SP - 87

EP - 93

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

SN - 1941-3149

IS - 1

ER -