Genetic variations associated with sudden cardiac death

Sudden cardiac death (SCD), which results from abnormal cardiac rhythms, accounts for more than half of all cardiovascular deaths in the United States.  While genes responsible for rare inherited arrhythmias have been identified, genetic factors for SCD more applicable to the general population are largely unknown.  SCD therefore poses a public health challenge because the majority of victims have no antecedent signs of cardiac disease and currently cannot be identified as being at risk. The goal of the Preventing Sudden Cardiac Death Transatlantic Network is to identify risk factors, both genetic and environmental, for SCD.

A population-based study revealing new genetic variations associated with SCD was published in the February 24, 2009 issue of Circulation by network researchers Drs. Peter Spooner and Aravinda Chakravarti from Johns Hopkins University and Dr. Eduardo Marbán from Cedars-Sinai Medical Center, along with Dr. Bruce Psaty of the University of Washington in Seattle, (a member of the LINAT network), and other investigators from the University of Texas, Houston and Wake Forest University.

In an earlier study, the investigators searched for genetic variations that influenced the QT interval.  The QT interval is an indicator of cardiac repolarization, the return of cardiac cells to their baseline electrical state after each heartbeat.  The QT interval is a potentially valuable intermediate marker of SCD risk because it is easily measured from electrocardiograms, is genetically influenced, and very high and very low values are associated with SCD.  Among white adults from Germany and the United States, the investigators found that differences in QT interval length were associated with variations in the NOS1AP (nitric oxide synthase 1 adaptor protein) gene.  This was an unanticipated finding, as the NOS1AP gene had not been previously implicated in determining the QT interval.   The NOS1AP gene encodes a protein called CAPON, which links the enzyme neuronal nitric oxide synthase with its targets and modulator proteins.  The investigators subsequently showed that CAPON influences the movement of calcium and potassium ions in cardiac cells, thus explaining how it could affect the QT interval.

In the present study, the investigators aimed to confirm, in a United States population of 14,737 whites and 4,558 blacks, that NOS1AP variants are associated with differences in the QT interval, and to determine whether these variants were also associated with SCD.  Subjects were followed for a median of 12 to 14 years.    Both white and black individuals who experienced SCD had signficantly longer QT intervals at baseline.  However, NOS1AP variants were associated with the QT interval and SCD only among whites.  Importantly, these variants did not change the risk for death from other cardiac or non-cardiac causes.  Thus, the increased risk due to the NOS1AP variant appears specific to SCD.

Thirty-nine percent of the general white population carries 1 copy of the NOS1AP risk variant, and 5% carry 2 copies.  Having 2 copies of the risk variant increases a person’s risk of SCD by 72% compared to someone with no copies.   A second NOS1AP variant, carried by 13% of the population, was found to be independently associated with a decreased risk in SCD.

This work represents an important step in developing an approach to SCD risk assessment in the general population.  Exploring the mechanisms of how NOS1AP variants increase SCD risk may also yield insight on new strategies to prevent SCD.

This research was also supported by the Donald W. Reynolds Foundation, the National Human Genome Institute and the National Institutes of Health.

Cick on the title to access the article in Circulation Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations