Abstract 16031: Tnni3k is a Novel Modulator of Cardiac Conduction
Mutations in cardiac ion channels lead to rhythm disorders associated with a high risk of sudden cardiac death. Incomplete penetrance and variable clinical expression complicate the management of patients with these disorders. As a result of our search for modifiers of disease severity, we have previously mapped a quantitative trait locus (QTL) on chromosome 3, which modulates the electrocardiographic PR-interval in F2 progeny of 129P2 and FVBN/J mice with the Scn5a1798insD/+ mutation. Since genetic variation underlying a QTL may affect the clinical phenotype through effects on gene expression, we carried out an expression QTL study (eQTL) to map genetic factors influencing transcript levels. We identified 16 eQTLs mapping within the 1.5 LOD interval of the PR QTL on Chr 3, seven of which were cis-eQTLs. Of these, Tnni3k, a gene that is highly expressed in heart was found to correlate to PR-interval (rho=0.28, p=0.003). Tnni3K expression is also significantly different in the wt founder lines FVBN/J and 129P2 corresponding to significantly different PR lengths (relative expression 129P2/(FVBN/J) = 8.8 p<0.002; PR: FVBN/J 32.5 ± 0.5 ms, n=26; 129P2 39.5 ± 0.6 ms, n=31; p<1e-10 ). Tnni3k encodes for troponin 1 cardiac-3 interacting kinase and was recently identified as a genetic modifier of disease progression in a mouse model of cardiomyopathy in an F2 cross of DBA/2J and AKR/J mice. To confirm the role of the Tnni3K locus in the regulation of PR duration we measured surface ECGs in DBA/2J, having low Tnni3K expression levels and DBA.AKR-Hrtfm2 congenic mice which have the AKR/J high expression locus for Tnni3K in a DBA/2J genetic background. These mice allow us to separate the role of the Tnni3K locus from the other genetic differences between the strains. As expected, the DBA/2J mice have a significantly shorter PR interval compared to the congenic mice (DBA/2J 32.8 ms ± 0.7 ms, n=12; congenic 40.2 ms ± 1.2 ms, n=11; p<0.0001). Our data provide evidence for a novel role of Tnni3K in controlling the electrocardiographic PR-interval, indicating a role for Tnni3K in atrial and/or atrio-ventricular conduction. This study was funded by the Netherlands Heart Foundation Established (NHS 2005T024) and the Inter-University Cardiology Institute of the Netherlands (ICIN 06401).
- © 2011 by American Heart Association, Inc.