Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease

Liyong Wang, Elizabeth R. Hauser, Svati H. Shah, Margaret A Pericak-Vance, Carol Haynes, David Crosslin, Marco Harris, Sarah Nelson, A. Brent Hale, Christopher B. Granger, Jonathan L. Haines, Christopher J H Jones, David Crossman, David M Seo, Simon G. Gregory, William E. Kraus, Pascal Goldschmidt-Clermont, Jeffery M Vance

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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.

Original languageEnglish
Pages (from-to)650-663
Number of pages14
JournalAmerican Journal of Human Genetics
Volume80
Issue number4
DOIs
StatePublished - Apr 1 2007

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Chromosome Mapping
Coronary Artery Disease
Single Nucleotide Polymorphism
Genes
rho GTP-Binding Proteins
Aorta
Atherosclerosis
Datasets
Chromosomes, Human, Pair 21
Guanine
Nitric Oxide Synthase Type II
African Americans
Alleles
Odds Ratio
Genotype

ASJC Scopus subject areas

  • Genetics

Cite this

Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. / 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 M; Gregory, Simon G.; Kraus, William E.; Goldschmidt-Clermont, Pascal; Vance, Jeffery M.

In: American Journal of Human Genetics, Vol. 80, No. 4, 01.04.2007, p. 650-663.

Research output: Contribution to journalArticle

Wang, L, Hauser, ER, Shah, SH, Pericak-Vance, MA, Haynes, C, Crosslin, D, Harris, M, Nelson, S, Hale, AB, Granger, CB, Haines, JL, Jones, CJH, Crossman, D, Seo, DM, Gregory, SG, Kraus, WE, Goldschmidt-Clermont, P & Vance, JM 2007, 'Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease', American Journal of Human Genetics, vol. 80, no. 4, pp. 650-663. https://doi.org/10.1086/512981
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 M ; Gregory, Simon G. ; Kraus, William E. ; Goldschmidt-Clermont, Pascal ; Vance, Jeffery M. / Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. In: American Journal of Human Genetics. 2007 ; Vol. 80, No. 4. pp. 650-663.
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AU - Wang, Liyong

AU - Hauser, Elizabeth R.

AU - Shah, Svati H.

AU - Pericak-Vance, Margaret A

AU - Haynes, Carol

AU - Crosslin, David

AU - Harris, Marco

AU - Nelson, Sarah

AU - Hale, A. Brent

AU - Granger, Christopher B.

AU - Haines, Jonathan L.

AU - Jones, Christopher J H

AU - Crossman, David

AU - Seo, David M

AU - Gregory, Simon G.

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N2 - 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.

AB - 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.

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