Original Investigation

Human Genetics

, Volume 127, Issue 5, pp 513-523

First online:

Kalirin: a novel genetic risk factor for ischemic stroke

  • Tiago KrugAffiliated withInstituto Gulbenkian de CiênciaInstituto de Medicina Molecular
  • , Helena MansoAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Liliana GouveiaAffiliated withServiço de Neurologia, Hospital de Santa Maria
  • , João SobralAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Joana M. XavierAffiliated withInstituto Gulbenkian de CiênciaInstituto de Medicina Molecular
  • , Isabel AlbergariaAffiliated withInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Gisela GasparAffiliated withInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Manuel CorreiaAffiliated withServiço de Neurologia, Hospital Geral de Santo António
  • , Miguel Viana-BaptistaAffiliated withServiço de Neurologia, Hospital Garcia de Orta
    • , Rita Moiron SimõesAffiliated withServiço de Neurologia, Hospital Fernando Fonseca
    • , Amélia Nogueira PintoAffiliated withServiço de Neurologia, Hospital Fernando Fonseca
    • , Ricardo TaipaAffiliated withServiço de Neurologia, Hospital Geral de Santo António
    • , Carla FerreiraAffiliated withServiço de Neurologia, Hospital São Marcos
    • , João Ramalho FontesAffiliated withServiço de Neurologia, Hospital São Marcos
    • , Mário Rui SilvaAffiliated withServiço de Neurologia, Hospital de São Pedro
    • , João Paulo GabrielAffiliated withServiço de Neurologia, Hospital de São Pedro
    • , Ilda MatosAffiliated withServiço de Neurologia, Hospital Distrital de Mirandela
    • , Gabriela LopesAffiliated withServiço de Neurologia, Hospital Geral de Santo António
    • , José M. FerroAffiliated withServiço de Neurologia, Hospital de Santa Maria
    • , Astrid M. VicenteAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge
    • , Sofia A. OliveiraAffiliated withInstituto Gulbenkian de CiênciaInstituto de Medicina Molecular Email author 

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Abstract

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.