Abstract 3564: A Multi-Stage Evaluation of Genetic Association with Early-Onset Coronary Artery Disease in MYLK Gene
Background: Consistent linkage evidence has been found for coronary artery disease (CAD) at chromosome 3q13–21. To fine map the region, we previously conducted a peak-wide association survey using single nucleotide polymorphisms (SNPs) evenly spaced at 100 kb intervals. While strongest association was found at Kalirin gene, multiple genes displayed evidence for association with early-onset CAD, including the myosin light chain kinase (MYLK) gene. MYLK is a member of the Kalirin-RhoGTPase pathway that we have proposed previously to be important in CAD.
Methods: To thoroughly evaluate the association at MYLK, we examined 46 tagging and functional SNPs across the gene in a case-control dataset with early-onset CAD (N=750), resulting in an average density of one SNP every 6 kb. Significant results were then validated in families with early-onset CAD (N=2954). As a third evaluation, the probands (N=560) of the families were compared to the controls (N=291) from the case-control dataset. Finally, validated SNPs were examined for correlation with atherosclerosis in 145 aorta specimens.
Results: Multiple SNPs were significant in the initial screening in the case-control dataset (p=0.001 to 0.038). However, only three of them were validated in all datasets (p=0.001 to 0.046). In addition, the risk alleles of the three SNPs were correlated with higher atherosclerosis burden in aortas (p=0.007 to 0.040). The three SNPs are in linkage disequilibrium with each other (r2>0.9) and span over 50 kb region near the 5’ end of the gene.
Conclusions: Our multi-stage evaluation strongly supports MYLK as a novel CAD susceptibility gene. MYLK regulates smooth muscle cell contraction and endothelial cell permeability through catalyzing the phorsphorylation of the regulatory myosin light chain. The known functions of MYLK provide a plausible mechanism for its involvement in the development of atherosclerosis.