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While you probably know "by heart" the rhythms of a favorite song, you might seldom hear, much less memorize, your heart's own endless cadence. In sudden cardiac death — when the heart basically stops, often with little or no obvious warning — the dynamics of the heartbeat can be an important, though seemingly subtle, forewarning that things are amiss. By seeking out the genes that help control the pace of the heartbeat, scientists may now have new insights that could help to explain this insidious condition.

An international team of scientists has identified a possible causal variation in NOS1AP, a gene known to regulate nitric oxide signaling in neurons, by correlating measurements of the heart's rhythmic contraction (the "QT interval") with the suite of genetic differences contained in the DNA of nearly 4,000 human subjects. As described in the April 30 online edition of Nature Genetics, the NOS1AP gene is particularly notable because it has not been previously associated with sudden cardiac death. This work signifies a whole genome approach to understanding an obscure and quiet killer, and has opened up an avenue of cardiac biology that may not have been otherwise discovered.

To pump blood effectively throughout the body, the heart must contract and relax in a timely yet rhythmic manner. The QT interval marks a "repolarization phase," a time during which cardiac muscle cells replenish the electrical resources needed to drive the heart's contraction. This period represents a quantitative trait that, similar to height, varies along a continuous spectrum among different individuals, and it is likely influenced by a host of both genetic and environmental factors. For example, an abnormally long or short QT interval, which can be detected through an electrocardiogram (ECG), can precipitate the sometimes fatal heart arrhythmias that underlie sudden cardiac death.

A team including Ó³»­´«Ã½ scientists Chris Newton-Cheh, Chris O'Donnell, and Joel Hirschhorn, and led by researchers at Johns Hopkins University, sought to identify the common genetic factors that abbreviate or extend the QT interval, thereby predisposing individuals to sudden cardiac death. They screened the DNA of ~4,000 German patients enrolled in the KORA study using a three-staged approach that incorporated both candidate gene and genome-wide methods. This entailed a survey of 115,000 single nucleotide polymorphisms (SNPs) in 200 female patients drawn from the farthest ends of the QT interval range. By excluding males from this initial analysis, the researchers could minimize the confounding effects of cardiovascular disease, which is generally more prevalent in males, and avoid the sex-related differences inherent to the QT interval. They then re-screened the most promising SNPs in two subsequent rounds of analysis, which included larger numbers of patients (and added males to the final round) with QT intervals that successively approached a typical value.

The researchers identified seven significant SNPs, which were subsequently pursued in genetic analyses of two additional populations: a second, unrelated group of more than 2,600 individuals from the KORA study and a cohort of about 1,800 participants in the Framingham Heart Study. This replication effort confirmed that the most significant genetic association to sudden cardiac death, using the described methodology, lies within the NOS1AP gene. The known role for this gene, which has not been previously associated with sudden cardiac death, involves the regulation of nitric oxide levels in neurons and represents an aspect of cellular physiology that has not been previously associated with the condition. While the identified variant in NOS1AP has indeed launched a new and intriguing area for future study, it accounts for just a small percentage of the total variability in the QT interval among the sampled populations. Therefore, there are likely a few, and perhaps many, additional variants that help to appropriately time the heartbeat, which remain to be uncovered in the human genome.