title: 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.
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke Univeristy Medical Center, Durham, NC, USA.
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: David
authors.initials: D
authors.lastname: Crosslin
authors.forename: Marco
authors.initials: M
authors.lastname: Harris
authors.forename: Sarah
authors.initials: S
authors.lastname: Nelson
authors.forename: A Brent
authors.initials: AB
authors.lastname: Hale
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Crossman
authors.forename: David
authors.initials: D
authors.lastname: Seo
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta / Q000473:pathology; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases