Identification of Kalirin gene as a novel coronary artery disease gene through peak-wide association mapping on chromosome 3q13-21. L. Wang¹, E.R. Hauser¹, S.H. Shah^1,2, C. Haynes¹, M. Harris¹, J. Rombaut¹, D. Crosslin¹, S. Nelson¹, A.B. Hale¹, S.G. Gregory¹, W.E. Kraus², M. Pericak-Vance¹, P.J. Goldschmidt-Clermont^2,3, J.M. Vance¹, GENECARD. Investigators^1,4,5,6. 1) Ctr Human Genetics, Duke Univ Medical Ctr, Durham, NC; 2) Dept of Med and Division of Cardiology, Duke Univ Medical Ctr, Durham, NC; 3) Miller School of Med, Univ of Miami, Miami, FL; 4) Vanderbilt Univ, Nashville, TN; 5) Univ of Wales College of Med, Cardiff, UK; 6) Univ of Sheffield, Sheffield, UK.
   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) underneath the linkage peak marker was associated with severe CAD. Herein, we completed a peak-wide association mapping using two independent Caucasian case-control datasets (CATHGEN, initial and validation) to see if additional loci were contributing to this region. 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 findings (p<0.05) were evaluated in additional datasets, including a family-based dataset (N=2954), an African-American case-control set (N=220), and a population-based Caucasian control set (N=255). The association between SNP and atherosclerosis was examined in 140 human aortas. Peak-wide survey found 3 SNPs in Kalirin gene to be associated with early-onset CAD (age-at-onset<55) in both CATHGEN datasets (p<0.05). Further genotyping in the gene found that rs9289231 was associated with early-onset CAD in all datasets (p<0.05). In the joint analysis of 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. In addition, the risk allele of this SNP was associated with atherosclerosis burden (p=0.03). Kalirin gene was associated with CAD in multiple independent datasets (N>4000). Kalirin is a protein with many functions, including the inhibition of inducible nitric oxide-synthase. Our data suggest that Kalirin is a novel candidate gene for CAD susceptibility.