Abstract 16115: Artioventricular Conduction Time in Mice; Hcls1 is a Candidate Gene
Introduction Changes in atrioventricular conduction time (PR-interval) can indicate an increased risk of important cardiac dysfunctions, including atrial fibrillation. Therefore, understanding the genetics of PR-interval could have important clinical implications. The present study identified a quantitative trait locus (QTL) associated with differences in PR-interval between recombinant inbred (RI; AXB/BXA) mice.
Methods 28 AXB/BXA RI and parental strains (8-12 wks; 20-30g; n=4/strain) were instrumented with an ETA-F20 (DSI) transmitter. ECG was recorded continuously for 30 minutes from quiescent mice. PR-interval was measured using specialist software (Ponemah v4.8). QTL mapping was performed using Web QTL (www.genenetwork.org).
Results Significant differences in PR-interval were found between strains (range 0.03 ± 0.0001 (AXB5) vs. 0.04 ± 0.0003 ms (BXA2) and the distribution of PR-intervals was continuous suggesting a complex trait. A significant QTL was identified on chromosome 16 (peak LRS = 18.7), which exceeded significance (LRS = 16.3) between 26.0 and 27.4Mb. We narrowed our search for candidate genes by selecting genes with informative non-synonymous single nucleotide polymorphisms (SNPs) using the Mouse Phenome Database (http://phenome.jax.org). A candidate gene with this criteria and near the chromosome 16 QTL at 36.94Mb (LRS = 9.009) is hematopoietic cell specific Lyn substrate 1 (Hcls1) which has a non-synonymous coding SNP (G/A) resulting in a G/T substitution and the A genotype had significantly higher PR-intervals compared to the G genotype (P = <0.01).
Discussion PR-interval QTLs in human and animal models have been reported suggesting the genetics of PR-interval are complex. The QTL we present here has not been reported before in mice or a syntenic region in other species and therefore may help to further explain the genetic basis for PR-interval. Hcls1 is highly expressed in cardiomyocytes and is involved in mitochondrial function. HCLS1 is a synthase responsible for the production of an abundant phospholipid in the myocardium, cardiolipin. An association between metabolic gene disorders is well established and therefore Hcls1 variants may have important clinical implications for PR-interval.
- © 2011 by American Heart Association, Inc.