Kalirin: a novel genetic risk factor for ischemic stroke.
Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.
Krug
Tiago
T
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Manso
Helena
H
Gouveia
Liliana
L
Sobral
João
J
Xavier
Joana M
JM
Albergaria
Isabel
I
Gaspar
Gisela
G
Correia
Manuel
M
Viana-Baptista
Miguel
M
Simões
Rita Moiron
RM
Pinto
Amélia Nogueira
AN
Taipa
Ricardo
R
Ferreira
Carla
C
Fontes
João Ramalho
JR
Silva
Mário Rui
MR
Gabriel
João Paulo
JP
Matos
Ilda
I
Lopes
Gabriela
G
Ferro
José M
JM
Vicente
Astrid M
AM
Oliveira
Sofia A
SA
D000328:Adult; D017668:Age of Onset; D000368:Aged; D002545:Brain Ischemia / Q000150:complications*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology* / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics*
D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C404565:ROPN1 protein, human; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins