Common Polymorphisms in &lt;i&gt;KNCJ5&lt;/i&gt; Are Associated with Early-Onset Lone Atrial Fibrillation in Caucasians

Jabbari, Javad; Olesen, Morten S.; Holst, Anders G.; Nielsen, Jonas B.; Haunsø, Stig; Svendsen, Jesper Hastrup

doi:10.1159/000323840

Cited by 25 publications

(18 citation statements)

References 66 publications

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“…Control groups I and II were previously described in detail. 26,27 These control groups were used in the genotyping of rs6795970 using a Taqman assay. To increase the statistical power of our association study, we also used a third control cohort (control group III), comprising 6,161 individuals randomly selected from a Danish cohort study (Inter99, LuCamp).…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…Recent studies link GIRK1 to schizophrenia susceptibility in a Chinese population; 13 in this study, lower GIRK1 expression levels in post-mortem brains from schizophrenic and bipolar individuals were observed. Other studies have suggested GIRK2 and GIRK3's involvement in responsiveness to analgesics, 14,15 GIRK2's potential link to alcoholism, 16 as well as links between GIRK4 and early onset atrial fibrillation 17 and hyperaldosteronism. 18 Although GIRKs have long been the focus of basic research efforts providing mounting evidence to linkages to human disease, there are very few pharmacological tools that have been reported 19 that might allow a better understanding of the roles of GIRKs in normal and pathophysiological conditions.…”

Section: −3mentioning

confidence: 97%

ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice

Kaufmann¹,

Romaine²,

Days³

et al. 2013

ACS Chem. Neurosci.

134

156

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The G-protein activated, inward-rectifying potassium (K + ) channels, "GIRKs", are a family of ion channels (K ir 3.1-K ir 3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo-and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.

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“…76 An association between early-onset AF and 2 common polymorphisms in KCNJ5 has been reported. 77 However, since neither polymorphism results in an amino acid change, the implications of this finding are unclear. Mice with genetic ablation of Kir3.1 or Kir3.4 are viable and lack any I KACh current.…”

Section: Kir21mentioning

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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Common Polymorphisms in <i>KNCJ5</i> Are Associated with Early-Onset Lone Atrial Fibrillation in Caucasians

Cited by 25 publications

References 66 publications

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

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

ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice

Cardiac ion channels

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