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Human Genetics

, Volume 127, Issue 5, pp 513–523 | Cite as

Kalirin: a novel genetic risk factor for ischemic stroke

  • Tiago Krug
  • Helena Manso
  • Liliana Gouveia
  • João Sobral
  • Joana M. Xavier
  • Isabel Albergaria
  • Gisela Gaspar
  • Manuel Correia
  • Miguel Viana-Baptista
  • Rita Moiron Simões
  • Amélia Nogueira Pinto
  • Ricardo Taipa
  • Carla Ferreira
  • João Ramalho Fontes
  • Mário Rui Silva
  • João Paulo Gabriel
  • Ilda Matos
  • Gabriela Lopes
  • José M. Ferro
  • Astrid M. Vicente
  • Sofia A. Oliveira
Original Investigation

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.

Keywords

Ischemic Stroke iNOS Activity Complete Linkage Disequilibrium Impute Genotype Impute SNPs 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are deeply grateful to all study participants and to the genotyping unit at the Instituto Gulbenkian de Ciência. This work was supported in part by the Marie Curie International Reintegration Grant 513760 (SAO), the Marie Curie Intra-European Fellowship 024563 (SAO), the grant PTDC/SAU-GMG/64426/2006 from the Portuguese Fundação para a Ciência e a Tecnologia (FCT), and by fellowships from FCT (TK, HM), from the Portuguese Instituto do Emprego e Formação Profissional (TK, JX) and from Fundação AstraZeneca/Faculdade de Medicina de Lisboa (LG).

Supplementary material

439_2010_790_MOESM1_ESM.doc (52 kb)
Supplementary material (DOC 58 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Tiago Krug
    • 1
    • 2
  • Helena Manso
    • 1
    • 3
  • Liliana Gouveia
    • 4
  • João Sobral
    • 1
    • 3
  • Joana M. Xavier
    • 1
    • 2
  • Isabel Albergaria
    • 3
  • Gisela Gaspar
    • 3
  • Manuel Correia
    • 5
  • Miguel Viana-Baptista
    • 6
  • Rita Moiron Simões
    • 7
  • Amélia Nogueira Pinto
    • 7
  • Ricardo Taipa
    • 5
  • Carla Ferreira
    • 8
  • João Ramalho Fontes
    • 8
  • Mário Rui Silva
    • 9
  • João Paulo Gabriel
    • 9
  • Ilda Matos
    • 10
  • Gabriela Lopes
    • 5
  • José M. Ferro
    • 4
  • Astrid M. Vicente
    • 1
    • 3
  • Sofia A. Oliveira
    • 1
    • 2
  1. 1.Instituto Gulbenkian de CiênciaOeirasPortugal
  2. 2.Instituto de Medicina MolecularLisbonPortugal
  3. 3.Instituto Nacional de Saúde Dr. Ricardo JorgeLisbonPortugal
  4. 4.Serviço de NeurologiaHospital de Santa MariaLisbonPortugal
  5. 5.Serviço de NeurologiaHospital Geral de Santo AntónioPortoPortugal
  6. 6.Serviço de NeurologiaHospital Garcia de OrtaAlmadaPortugal
  7. 7.Serviço de NeurologiaHospital Fernando FonsecaAmadoraPortugal
  8. 8.Serviço de NeurologiaHospital São MarcosBragaPortugal
  9. 9.Serviço de NeurologiaHospital de São PedroVila RealPortugal
  10. 10.Serviço de NeurologiaHospital Distrital de MirandelaMirandelaPortugal

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