Genes and Atrial Fibrillation

Fatkin, Diane; Otway, Robyn; Vandenberg, Jamie I.

doi:10.1161/circulationaha.106.688889

Cited by 57 publications

(24 citation statements)

References 87 publications

(108 reference statements)

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“…The coding regions were amplified using polymerase chain reaction and sequenced with a 3100 BigDye Terminator v3.1 sequencing kit and ABI PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). We sequenced other AF-linked genes [ KCNE2 (NM172201), KCNE3 (NM005472), KCNE5 (NM012282), NPPA (NM006172), KCNA5 (NM002234), KCNJ2 (NM00891), GJA5 (NM005266 and 181703) , SCN1B (NM001037 and 199037), SCN2B (NM004588)] and SCN3B (NM018400) in the R231C-Q1 proband from the family with AF (Figure 1, Family A, subject II:1) (for review, see reference 16–20 ). We also compared 21 single nucleotide polymorphisms (SNPs) (including KCNE5 ) that alter AF susceptibility (rs1805123, rs1805120, rs1805127, rs1805124, rs2200733, rs10033464, rs35594137, rs12621643, rs1800872, rs583362, rs7193343, rs3807989, rs11708996, rs6800541, rs251253, rs5063, rs13376333, rs11047543, rs3825214, rs1801252, and rs17003955) among the families shown in Figure 1 (Online Supplemental Table 2).…”

Section: Methodsmentioning

confidence: 99%

R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation

et al. 2011

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BACKGROUND Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K+ channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype–phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation. OBJECTIVE The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF. METHODS The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (IQ1E1) were analyzed using the whole-cell patch-clamp technique. RESULTS Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active IQ1E1 and smaller maximal IQ1E1 compared to cells expressing WT-Q1. CONCLUSION Constitutively active IQ1E1 and a smaller peak IQ1E1 are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.

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Section: Methodsmentioning

confidence: 99%

R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation

et al. 2011

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“…4 Thus, common genetic variants play a role in the development of this multifactorial disease. 5 Several studies have shown PR-interval prolongation on an ECG to be an independent risk factor for developing AF. [6][7][8] Five independent GWAS publications have shown that genetic variants in SCN10A influence the PR-interval duration.…”

Section: Clinical Perspective P 73mentioning

confidence: 99%

Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation

Jabbari

Olesen

Yuan

et al. 2015

Circ Cardiovasc Genet

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2=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 ). 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. (Circ Cardiovasc Genet. 2015;8:64-73.

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“…4 Thus, common genetic variants play a role in the development of this multifactorial disease. 5 Several studies have shown PR-interval prolongation on an electrocardiogram to be an independent risk factor for developing AF. 6–8 Five independent GWAS publications have shown that genetic variants in SCN10A influence the PR-interval duration.…”

Section: Introductionmentioning

confidence: 99%

Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation

Jabbari¹,

Olesen²,

Yuan³

et al. 2015

Circulation: Cardiovascular Genetics

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Background Genome-wide association studies (GWAS) have shown that the common single nucleotide polymorphism (SNP) rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR–interval prolongation and atrial fibrillation (AF). SNP rs6800541 is in high linkage disequilibrium with the non-synonymous 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 SNP variant, we included 515 AF patients, and two control cohorts of 730 individuals free of AF and 6,161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, nine rare missense variants and one 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=2.3×10−05). Both of the common variants, A1073 andP1092, induced a gain-of-channel function, while 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 impact 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.

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Genes and Atrial Fibrillation

Cited by 57 publications

References 87 publications

R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation

R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation

Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation

Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation

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