Heart: International Effort Finds Out New Genetic Variants Associated With QT Interval

Main Category: Heart Disease
Also Included In: Cardiovascular / Cardiology;  Genetics
Article Date: 24 Mar 2009 - 3:00 PDT

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Italian scientists of the Institute of Neurogenetics and Neurofarmacology (INN) of the National Research Council (CNR) in Cagliary, Italy, working with international scientists of the QTSCD (QT interval and Sudden Cardiac Death) consortium, have identified nine novel genetic variants implicated in the regulation of QT interval, a measure of cardiac repolarization obtained from an analysis of the electrocardiogram (EKG), while confirming the role of the recently discovered NOS1AP gene.

Studies of the QT interval from the electrocardiogram (EKG), which captures major temporal and spatial aspects of the repolarization process, are particularly attractive as its prolongation or shortening reflects alterations of cardiac repolarization known to trigger ventricular tachycardia and ventricular fibrillation and predispose to sudden cardiac death (SCD). Importantly, QT interval prolongation has been associated with increased cardiovascular mortality in individuals with heart disease, as well as in the general population.

"Although several risk factors are known to prolong QT interval, including being female gender, age or some drugs, the genetic component has a key role", says Serena Sanna, statistical geneticist of the INN-CNR, who conducted the study in collaboration with Arne Pfeufer, M.D., group leader at the Institute of Human Genetics at the Technical University in Munich, Germany, and Dan Arking, PhD, assistant professor at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA, along with other members of SardiNIA/ProgeNIA, KORA, ARIC, HNR and GenNova studies.

"If we know the genes associated with QT interval we can study their function and thus better understand the underlying biological and chemical mechanisms that regulate the cardiac repolarization", says Aravinda Chakravarti, professor at the McKusick-Nathans Institute for Genetic Medicine at Hopkins, senior author of the report. "More immediately, our results point to a specific set of loci that are associated with QT interval and provide further targets for molecular studies of susceptibility to QT-triggered ventricular arrhythmias, sudden cardiac death and cardiovascular function in general."

To identify genetic variants that modulate QT interval, researchers used a relatively new approach, known as a genome-wide association study (GWAS). The GWAS strategy enables researchers to survey the entire human genetic blueprint, or genome. The human genome contains approximately 3 billion base pairs, or letter, known as nucleotides. Each person's genome differs from the next person's by as many as 10 million nucleotides. The researchers looked for single nucleotide variations - known as single nucleotide polymorphisms (SNPs) - that track with having longer or shorter QT interval.

"We pooled the information of thousand individuals from Sardinia, Germany, South Tyrol and United States and used advanced bio-statistical methods to identify which of the 2 million variants analyzed was associated with variations of QT interval", says Gonçalo R. Abecasis, D.Phil., co-senior author of the report and statistical geneticist of the University of Michigan's School of Public Health. He remarks that "This study also demonstrates the power of international collaboration in genetic analyses. None of the studies that cooperated to make this work possible were large enough to find all of these important associations alone. By working together, we were able to reach the necessary statistical power needed to identify the nine novel genetic variants."

An additional take-home lesson from this study is that "We demonstrated that GWAS for quantitative traits on community-based studies can suggests genomic region that may be directly involved in diseases. Indeed, four of the ten loci we identified by association overlap with genes known to harbor mutations causing Long-QT and Short-QT syndromes" says Manuela Uda, scientist of the INN-CNR and principal investigator of the SardiNIA project, known in Italy as the ProgeNIA project. "The SardiNIA project is a collaborative effort of nurses, physicians, statisticians, biologists and computer scientists working in Lanusei and Cagliari, who are greatly thankful to the volunteers who participated in the project". The SardiNIA investigators contributed to the discovery of several genes, as those associated with lipid concentration, height, osteoarthritis, obesity, arterial stiffness and thyroid function.

The SardiNIA project is funded by the National institute of aging (NIA); the GenNova project is funded by the Provincia Autonoma di Bolzano Alto Adige and by Fondazione Cassa di Risparmio di Bolzano; the ARIC project is funded by the following: National Human Genome Research Institute (NHGRI), National Heart Lung and Blood Institute (NHLBI), National Human Genome Research Institute (NHGR), National Institutes of Health (NIH); the KORA study is funded by the by grants by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET) and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) Ministero Federale dell'Educazione e Ricerca Tedesco (BMBF) and the HNR Study was funded by a grant of the Heinz Nixdorf Foundation.

In summary

Who: scientists of the Institute of Neurogenetics and Neurofarmacology (INN) of the National Research Council (CNR) in Cagliary, Italy.

What: identified nine novel genetic variants implicated in the regulation of QT interval

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