Expression Levels of the Gene in the Heart Are Highly Associated with Cardiac and Glucose Metabolism-Related Phenotypes and Functional Pathways.

Background: Troponin-I interacting kinase encoded by the gene is expressed in nuclei and Z-discs of cardiomyocytes. Mutations in were identified in patients with cardiac conduction diseases, arrhythmias, and cardiomyopathy.

Methods: We performed cardiac gene expression, whole genome sequencing (WGS), and cardiac function analysis in 40 strains of BXD recombinant inbred mice derived from C57BL/6J (B6) and DBA/2J (D2) strains. Expression quantitative trait loci (eQTLs) mapping and gene enrichment analysis was performed, followed by validation of candidate -regulatory genes.

Results: WGS identified compound splicing and missense T659I variants in the D2 parent and some BXD strains (D allele) and these strains had significantly lower expression than those carrying wild-type (B allele). Expression levels of significantly correlated with multiple cardiac (heart rate, wall thickness, PR duration, and T amplitude) and metabolic (glucose levels and insulin resistance) phenotypes in BXDs. A significant -eQTL on chromosome 3 was identified for the regulation of expression. Furthermore, -correlated genes were primarily involved in cardiac and glucose metabolism-related functions and pathways. Genes , , , , , , , , , , , and were differentially expressed between the B and D alleles.

Conclusions: Compound splicing and T659I variants reduce cardiac expression and levels are associated with cardiac and glucose metabolism-related phenotypes.