Scientists at deCODE genetics today report the discovery of seven novel and common single-letter variations in the sequence of the human genome (SNPs) that are involved in modulating the electrical impulses that govern the working of the heart. Two of these SNPs, which correlate with electrocardiogram (ECG or EKG) measurements that are used in the clinical evaluation of heart health and activity, were then shown to confer increased risk of atrial fibrillation (AF), one of the most common causes of irregular heartbeat and a leading cause of stroke. The paper, “Several common variants modulate heart rate, PR interval and QRS duration,” is published online in Nature Genetics and will appear in an upcoming print addition of the journal.

The deCODE team began by correlating ECG measurements with genome-wide SNP data from more than 40,000 Icelandic participants in its gene discovery program. This search identified one novel SNP influencing heart rate and four each linked to PR interval and QRS duration, measurements of how quickly the electrical impulses that cause the heart muscles to pump achieve their purpose. Intriguingly, SNPs on chromosome 3 linked to both longer PR interval and QRS duration are in the gene encoding SCN10A, a sodium channel that has never before been linked to heart activity. Individuals with the same variants were also more likely to have been fittted with a pacemaker. A follow-on analysis of all of the novel SNPs in Icelandic and Norwegian heart patients and controls demonstrated the association of two of the SNPs linked to PR interval to risk of AF, and another SNP to increased risk of advanced atrioventricular block. Two other papers published today in the same journal provide further validation of some of the deCODE findings.

“Over the past two years, we have discovered major genetic risk factors for heart disease and stroke and introduced tests for these risk factors into clinical practice. We are building the power of these tests through our ongoing discovery work, and today’s findings demonstrate again the fruitfulness of using intermediate risk factors and clinical measurements as entry points for finding risk factors for disease. Our population resources enable us to do so efficiently and with exciting results. These latest findings will be incorporated into our deCODE AF test and deCODEme scans,  and certain of these discoveries may also provide opportunities for out-licensing for therapeutic development,” said Kari Stefansson, CEO of deCODE.

deCODE Discovers Second Common Genetic Risk Factor for Atrial Fibrillation and Stroke. Will be integrated into deCODE AF™ DNA-based risk assessment test, and into the deCODEme™ and deCODEme Cardio™ scans.

Scientists at deCODE genetics and colleagues from Europe and the United States today report the discovery of a common single-letter variant in the sequence of the human genome (SNP) conferring increased risk of atrial fibrillation (AF) and stroke. The findings will be integrated directly into the deCODE AF™ reference laboratory test for gauging individual risk of AF and stroke and helping to identify stroke patients who may benefit from enhanced monitoring for AF. The study is published online today in Nature Genetics.

The new SNP is in the ZFHX3 gene on chromosome 16q22, and the more than one third of people of European descent who carry one copy are at approximately 20% greater risk of AF and cardioembolic stroke than are individuals who carry none. AF is the most common type of cardiac arrhythmia, and is a major risk factor for stroke. Because AF is often intermittent and difficult to detect, gauging genetic susceptibility can help doctors to decide which of their stroke patients might benefit from longer-term monitoring for AF following a stroke. Those with stroke due to AF may be given different therapy than they would otherwise. This is the purpose of deCODE AF™, at the heart of which is the major AF and stroke variant discovered by deCODE on 4q25. Indeed today’s findings are the result of deCODE’s program to build on this work and to find new risk variants. After expanding their genome-wide association study in Iceland, the deCODE team took the top SNPs outside the 4q25 region and typed them in case-control cohorts from Iceland, Norway and the United States. This confirmed the ZFHX3 SNP as a risk variant for AF. Analysis in stroke cohorts from Iceland, Germany, Sweden and the UK demonstrated that this SNP was associated with increased risk of stroke, particularly cardioembolic stroke.

“This is an important discovery and all the more gratifying because we can integrate it straight into a test that is already helping to improve patient care in the clinic.
As with our 4q25 variant, this latest discovery has been replicated in numerous populations by us and others, and the connection to cardioembolic stroke is yet further evidence that we are putting our finger on an important pathway involved in AF and stroke risk. The ability to routinely test for these risk factors means that we can understand whom we should screen intensively for AF and then prescribe the drugs most suited to the cause of a particular patient’s disease. This is the sort of personalized medicine that genetics is enabling – individualized care that may mean not only better outcomes but significant potential savings to the healthcare system. Discoveries like this are the foundation upon which this transformation is being made,” said Kari Stefansson, CEO of deCODE.

deCODE and the authors wish to thank the participants who took part in this study and made it possible. Financial support for this study was provided by US National Institutes of Health grants HL075266 and U01 HL65962 and American Heart Association grant 0940116N; by the German Federal Ministry of Education and Research (01GI9909/3), by the German Migraine & Headache Society (DMKG), and by unrestricted grants of equal share from Astra Zeneca, Berlin Chemie, Boots Healthcare, Glaxo-Smith-Kline, McNeil Pharma, MSD Sharp & Dohme and Pfizer to the University of Muenster.

deCODE genetics and Celera Corporation have announced the signing of agreements under which deCODE has granted Celera non-exclusive worldwide licenses to deCODE’s genetic markers for increased risk of major cardiovascular and metabolic diseases, including heart attack, stroke, atrial fibrillation (AF) and type 2 diabetes (T2D). These markers can be incorporated into laboratory tests for assessing and managing individual risk of these diseases.

“This is an excellent opportunity to broaden the clinical application and commercialization of our discoveries of high-impact genetic risk factors for major diseases. The markers included in these agreements are among the most widely replicated genetic risk factors for cardiovascular and metabolic disease, and they provide a natural complement to the biomarker services already offered by Berkeley HeartLab, Celera’s subsidiary.  In Celera we have a partner with a global reputation in human genetics and a large and effective outreach and sales force. We are pleased to have the chance to work with them to build upon our discovery and testing platforms and to accelerate the adoption of personalized medicine,” said Kari Stefansson CEO of deCODE.

“We believe access to these highly replicated markers, which complement our internal proprietary genetic discoveries in cardiovascular disease such as KIF6 and LPA, furthers Celera’s commitment to be a leading provider of genetic tests used routinely in personalizing disease management,” said Kathy Ordoñez, CEO of Celera.  “We expect Berkeley HeartLab to incorporate these markers into future laboratory service offerings, and Celera plans to ultimately commercialize them globally as new molecular diagnostic tests through our Products business.  We believe these markers that predict risk of coronary heart disease and drug response could produce highly differentiated, proprietary, and compelling tests that personalize cardiovascular disease management.”