Editors' ChoiceAtrial Fibrillation

Quieting the Quivering Heart

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Science Translational Medicine  03 Feb 2010:
Vol. 2, Issue 17, pp. 17ec17
DOI: 10.1126/scitranslmed.3000892

The 2.3 million Americans afflicted with atrial fibrillation (AF)—the most common abnormal heart rhythm—face a daunting future that includes a heightened risk for stroke, heart failure, and death. Because the risk for AF increases with age, the prevalence of this disease is expected to increase fivefold as life expectancies increase worldwide. A better understanding of the genetic underpinnings of the disease may be at hand, offering hope for the development of new therapies. In 2007, sequence variants near the PITX2 gene, which has a role in cardiac development, were implicated in AF. Heterozygous carriers—about 30% of Europeans—have an approximately twofold increase in disease susceptibility relative to those without the variants.

Now, two independent studies of separate populations shed further light on AF genomics. Using a genome-wide association (GWA) approach, investigators assayed thousands of sequence variations in tens of thousands of cases and controls for correlations between variants and changes in the heart’s electrical activity as measured with electrocardiograms. Nine variants correlated with abnormalities in the PR interval, which is a fraction of one heartbeat. Further, when these variants were independently tested in a separate cohort, five of them were significantly associated with AF. Strikingly, the variants are in cardiac development and ion channel genes and are of plausible biological significance in AF, which is in stark contrast to the unknown functional significance of many loci linked to complex traits through GWA studies. Such an approach exemplifies the power to illuminate critical biological pathways in complex traits by using important intermediate phenotypes. Going forward, these results should translate to greater insight into the root cause of this troublesome disease.

H. Holm et al., Several common variants modulate heart rate, PR interval and QRS duration. Nat. Genet. 42, 117–122 (2010). [Abstract]

A. Pfeufer et al., Genome-wide association study of PR interval. Nat. Genet. 42, 153–159 (2010). [Abstract]

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