Peakwide Mapping on Chromosome 3q13 Identifies the Kalirin Gene as a Novel Candidate Gene for Coronary Artery Disease

Abstract

A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13-21 in a linkage study of early-onset CAD. We completed an association-mapping study across the 1-LOD-unit-down supporting interval, using two independent white case-control data sets (CATHGEN, initial and validation) to evaluate association under the peak. Single-nucleotide polymorphisms (SNPs) evenly spaced at 100-kb intervals were screened in the initial data set (N=468). Promising SNPs (P<.1) were then examined in the validation data set (N=514). Significant findings (P<.05) in the combined initial and validation data sets were further evaluated in multiple independent data sets, including a family-based data set (N=2,954), an African American case-control data set (N=190), and an additional white control data set (N=255). The association between genotype and aortic atherosclerosis was examined in 145 human aortas. The peakwide survey found evidence of association in SNPs from multiple genes. The strongest associations were found in three SNPs from the kalirin (KALRN) gene, especially in patients with early-onset CAD (P=.00001-00028 in the combined CATHGEN data sets). In-depth investigation of the gene found that an intronic SNP, rs9289231, was associated with early-onset CAD in all white data sets examined (P<.05). In the joint analysis of all white early-onset CAD cases (N=332) and controls (N=546), rs9289231 was highly significant (P=.00008), with an odds-ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P=.03) in 145 human aortas. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase and guanine-exchange-factor activity. KALRN and two other associated genes identified in this study (CDGAP and MYLK) belong to the Rho GTPase-signaling pathway. Our data suggest the importance of the KALRN gene and the Rho GTPase-signaling pathway in the pathogenesis of CAD.

Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people

“…rs11881940T was observed to be a protective factor for CAD; this allele may alter a conserved adenine in a putative interferon-regulatory factor-1-binding site, affecting the incidence of CAD. Connelly et al (2006), studying a Caucasian population, found that the alleles rs3803 and rs2713604 of the transcription factor GATA2 (Wang et al, 2007) CAD. We observed that rs3803 was a CAD-protective factor.…”

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

“…For example, CDGAP properties are well conserved between human and mouse species, and CDGAP may play an unexpected role in apoptosis and has suggestive association with coronary artery disease. 36,37 In the present study, SLC4A4 at position 4q21 showed maternal transmissions, and this gene encodes a sodium bicarbonate cotransporter involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with cystic fibrosis.…”

Kalirin: a novel genetic risk factor for ischemic stroke

“…These polymorphisms are located in ROPN1, ROPN1-KALRN intergenic region and in the 5Ј region of the KALRN gene. In our dataset, all of these polymorphisms are also haplotype tagging SNPs, with the exception of rs7613868 and rs12637456 (SNPs 7 and 9, respectively, in Wang et al 2007) which are in almost complete LD (r 2 = 0.97; Fig. 1).…”

“…We Wrst tested the association with IS of the 12 SNPs (Table 2), originally found associated with CAD in the CATHGEN initial dataset (SNPs 2, 3, 4, 7, 8, 9, 12, 14, 20, 22, 31, and 37 in Wang et al 2007), which includes the rs4234218 (SNP 31 in Wang et al 2007) associated with cardiovascular risk, T2D, and MS (Rudock et al 2008). These polymorphisms are located in ROPN1, ROPN1-KALRN intergenic region and in the 5Ј region of the KALRN gene.…”