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Genetic loci associated with abnormal heart rhythms
|Study:||Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction|
|By:||Sotoodehnia N. et al. (103 authors total)|
The researchers performed a meta-analysis of 14 genome-wide association studies covering 2.5 million SNPs in over 40,000 individuals of European descent. This was followed up with genotyping at nine loci in a further 7,000 individuals, also of European descent, as well as further computer and lab-based functional work.
The initial meta-analysis identified over 600 SNPs across 20 loci with genotyping in the additional cohort increasing this number to 22 loci. The most significantly associated locus, on chromosome 3p22, contained four independent associations, two in or near SCN10A and two in SCN5A, both sodium channel genes. Functional studies confirmed the involvement in producing heart beats of SCN10A, a gene that was only recently identified as being expressed in the heart.
The 22 identified loci include genes in pathways known to be involved in heart conduction as well as genes in pathways and processes not previously linked to heart conduction. The candidate gene, SCN10A, was shown to be expressed in the ventricular conduction system using a mouse model and that treatment with a SCN10A blocker prolongs the QRS duration. This study highlights the power of large genome-wide association studies in increasing the biological understanding of disease pathogenesis.
This study confirmed several known associations as well as discovering associations in pathways that were previously not known to play a role in heart conduction. The strongest association from the study SCN10A, a sodium channel gene, was shown to be a potential drug target for SCN10A blockers which alter the QRS duration. That SCN10A was only recently identified as being expressed in the heart and has now been shown to be amenable to drug manipulation, albeit in a mouse model, shows how quickly research can move forward. It will be interesting to see how follow up work in those candidate genes involved in processes not previously linked to heart electrophysiology progress.