Abstract 4108: Identification of Kalirin Gene as a Novel Coronary Artery Disease Gene through Peak-Wide Association Mapping on Chromosome 3q13-21
Background: A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13–21 in a linkage study. Previously, we reported that one gene (LSAMP) lying right underneath the linkage peak marker was associated with risk for left main CAD. Herein, we performed a thorough peak-wide association mapping using two independent Caucasian case-control datasets (CATHGEN, initial and validation) to see if additional loci were contributing to this large linkage peak.
Methods: Single nucleotide polymorphisms (SNPs) evenly spaced at 100 Kb intervals were screened in the initial dataset (N=372). Promising SNPs (p<0.1) were then examined in the validation dataset (N=383). Significant associations (p<0.05) were further evaluated in additional independent datasets, including a family-based dataset (N=2954), an African-American case-control dataset (N=220), and an additional population-based Caucasian control dataset (N=255). The association between genotype and aortic atherosclerosis was further examined in 110 human aorta samples collected from heart transplant donors.
Results: The most significant findings were located in the Kalirin gene. Peak-wide survey found three SNPs in the gene to be associated with early-onset CAD (age-at-onset<55) in both CATHGEN datasets (p<0.05). Additional genotyping in the gene found that an intronic SNP rs9289231 was associated with early-onset CAD in all additional datasets (p<0.05). In the joint analysis using all Caucasian early-onset CAD cases (N=461) and controls (N=619), rs9289231 was highly significant (p=0.0001) with an odds ratio estimate of 2.2. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden in the human aortas (p=0.03).
Conclusions: Kalirin gene was found to be associated with CAD in multiple independent datasets (total N>4000). Kalirin is a protein with many functions, including the inhibition of inducible nitric oxide-synthase. Our data suggest that Kalirin is a strong candidate gene for CAD susceptibility.