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

Content Provider	PubMed Central
Author	Wang, Liyong Hauser, Elizabeth R. Shah, Svati H. Pericak-vance, Margaret A. Haynes, Carol Crosslin, David Harris, Marco Nelson, Sarah Hale, A. Brent Granger, Christopher B. Haines, Jonathan L. Jones, Christopher J. H. Crossman, David Seo, David Gregory, Simon G. Kraus, William E. Goldschmidt-clermont, Pascal J. Vance, Jeffery M.
Copyright Year	2007
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.
Related Links	http://dx.doi.org/10.1086/512981
Ending Page	663
Page Count	14
Starting Page	650
File Format	PDF
ISSN	00029297
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	4
Volume Number	80
Language	English
Publisher	The American Society of Human Genetics
Publisher Date	2007-04-01
Access Restriction	Open
Rights Holder	The American Society of Human Genetics
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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