Community Research and Development Information Service - CORDIS

Final Report Summary - RISK FACTORS FOR SCD (Impact of the ionic channel and NOS1AP SNPs on the risk of cardiac events in Long QT Syndrome)

Cardiovascular disease is a leading cause of mortality worldwide. Approximately half of all cardiac deaths can be classed as sudden, and are due to severe disturbances in cardiac rhythm (ventricular tachycardia or fibrillation) that lead to a fatal cardiac arrhythmia.
Long QT syndrome (LQTS) is a rare hereditary cardiac disease characterized by a delay in the
ventricular repolarisation of the heart, with a detectable prolongation of the QT interval on the
electrocardiogram (ECG), leading to a risk of syncope and sudden death. The majority of patients
carry heterozygous mutations in the genes KCNQ1 (LQT1, 40-50%) and KCNH2 (LQT2, 35-45%), which
encode the alpha subunits of cardiac potassium ion channels responsible for cardiac repolarisation.
While many mutation carriers have syncope and are at risk of sudden death by ventricular fibrillation, others remain asymptomatic. Variable penetrance is a common theme for many LQTS mutations, and suggests an important role for other modifying or triggering factors. We aimed to investigate if specific single base-pair DNA changes, (single nucleotide polymorphisms, or SNPs) associated with a lengthened QTc (QT interval corrected for heart rate) in the normal population, can influence the course of disease in patients who have previously described causative mutations in ion channel genes.

We genotyped 25 selected SNPs in 112 family duos, consisting of one affected and one asymptomatic family member, both with the same LQT1 or LQT2 genotype. Population characteristics (age, gender, ethnicity, ECG parameters, treatment and history of cardiac events) were collected. Our goal was to determine whether SNP analysis could have a prognostic value for patient follow-up. We are currently in the process of analyzing our results, however, initial analysis suggests that only one coding SNP was significantly more frequent in the symptomatic group than in asymptomatic patient. Even if increased QTc appears to be linked to cardiac events, the combination of several SNPs previously reported to induce a small increase in QT duration through GWAS studies in the normal population do not appear to play a major role in influencing patient symptoms. We conclude so far that only the genotyping of KCNE1 D85N should be performed in all patients and could influence their risk of syncope and sudden death.
This research demonstrates progress in the field of SNP studies, and we envisage that with larger cohorts and faster and more efficient genotyping techniques, non-invasive ECG measurements coupled with detailed genetic SNP profiles will be able to increase the accuracy of risk assessment for cardiac events. This will aid in the prospective identification of those patients who carry protective or risk-enhancing SNPs. Availability of this information will make it possible to improve patients’ long term outcome via medication, pacemakers or defibrillator implantation.

Related information

Reported by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
France
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top