Ion channel mutations and atrial fibrillation

【Author】

VANDENBERG Jamie I;OTWAY Robyn;MANN Stefan;FATKIN Diane;

【Abstract】

<正>Atrial fibrillation is traditionally viewed as an acquired disease.However,a range of epidemiological studies has revealed that there is a clear familial component,indicating the influence of genetic factors.The relatively high prevalence of the disease and typically late onset with the presence of multiple co-morbid conditions has made it difficult to dissect out the genetic component and more importantly difficult to identify large kindreds that would facilitate linkage analysis.In this context,a number of groups working with small families(i.e.2-3 generations with 5-20 affected individuals)have adopted a candidate gene approach.This approach has focused on the role of ion channels,guided by work in the inherited ventricular arrhythmia syndromes that have been found to be due almost exclusively to mutations in ion channel genes.Mutations in a number of ion channel genes have now been associated with atrial fibrillation.However,none of the identified genes account for more than a few families. Therefore,there must be other genes and/or other modulating factors involved.The work in our laboratory has focused on the role of interactions between environmental factors and genetic predisposition to arrhythmias. Specifically,we are testing the hypothesis that gene mutations with minimal impact on function at baseline,may nevertheless alter the response to environmental stresses,i.e.these individuals when young would have normal baseline function but environmental stresses later in life(e.g.atrial dilatation secondary to hypertension)would elicit the arrhythmia phenotype.To date we have identified one ion channel mutation in a family that fulfils these criteria. Specifically a mutation in the N-terminal domain of KCNQ1 had normal function at baseline but an abnormal response to cell dilatation.Another approach that has been used to identify genetic factors in atrial fibrillation is the analysis of SNPs and haplotypes in large population groups.The advantage of this approach is that it is unbiased in terms of genes being examined,and recently led to the identification of the transcription factor Pitx2 as a candidate gene for the predisposition to atrial fibrillation.

【Keywords】

ion channel;;mutation;;atrial fibrillation;;genetic factors

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