Abstract 2183: Genetic Modifiers of ECG Manifestations in a Large Family With Cardiac Sodium Channel Disease
In the monogenic arrhythmia syndromes, extensive variability in clinical manifestations is observed among family members carrying an identical mutation. Important modifiers such as age, gender and drugs are already recognized, but while evidence points to a role for genetic modifiers in phenotypic variability, these remain largely unknown. In this study we carried out linkage analysis at chromosomal loci harboring 19 candidate genes involved in cardiac electrical activity in two large genealogically-linked kindreds with a SCN5A-1795insD mutation, for identification of loci modulating heart rate and ECG indices of conduction and repolarization. ECG, clinical data and DNA were available for 327 individuals (127 carriers). The candidate loci addressed harbor the genes: CASQ2, NOS1AP, RYR2, FKBP1B, CAV3, GPD1L, SCN5A, ANK2, AKAP9, KCNH2, KCNQ1, SCN4B, CACNA1C, KCNH4, SCN4A, KCNJ2, SCN1B, KCNE1, KCNE2. Individuals were genotyped at 1433 SNPs tagging common haplotype blocks (R2>0.8; minor allele frequency >10%) at these loci using the Golden Gate assay. Multipoint linkage analyses were performed using SOLAR. A LOD score >3.3 was considered genome-wide significant. As expected, ECG parameters for heart rate, atrial, atrio-ventricular and ventricular conduction, and repolarization, were found to be strongly linked to SNPs on chromosome. 3 in the region of the SCN5A mutation (LOD = 4.55–19.48). Upon correction for carrier-ship of the mutation, QTc was found to be modulated by chromosome 17 in the region of SCN4A and KCNJ2 (LOD=7.61) and the region containing KCNE1 and KCNE2 (LOD=4.38) on chromosome 21. Heart rate, P wave duration and PR interval were linked to chromosome 21 (KCNE2, KCNE1; LOD=3.13, 7.56, 4.05, respectively). PR interval was also linked to chromosome. 3 (CAV3; LOD=3.11). This study points to the presence of common genetic variation within several candidate genes that modulate heart rate, repolarization and conduction indices. In particular, it uncovers a role for KCNE1 and/or KCNE2, previously known to be only involved in cardiac repolarization, in control of heart rate and cardiac conduction. This effect could arise through direct or indirect effects on ion channels mediating the action potential upstroke.