Skip to main content
SpringerLink
Log in

Kalirin: a novel genetic risk factor for ischemic stroke

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed  Google Scholar 

  • Beresewicz M, Kowalczyk JE, Zabłocka B (2008) Kalirin-7, a protein enriched in postsynaptic density, is involved in ischemic signal transduction. Neurochem Res 33:1789–1794

    Article  CAS  PubMed  Google Scholar 

  • Bowden DW, Rudock M, Ziegler J, Lehtinen AB, Xu J, Wagenknecht LE, Herrington D, Rich SS, Freedman BI, Carr JJ, Langefeld CD (2006) Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes 55:1985–1994

    Article  CAS  PubMed  Google Scholar 

  • Chiodini BD, Lewis CM (2003) Meta-analysis of 4 coronary heart disease genome-wide linkage studies confirms a susceptibility locus on chromosome 3q. Arterioscler Thromb Vasc Biol 23:1863–1868

    Article  CAS  PubMed  Google Scholar 

  • Domingues-Montanari S, Mendioroz M, del Rio-Espinola A, Fernández-Cadenas I, Montaner J (2008) Genetics of stroke: a review of recent advances. Expert Rev Mol Diagn 8:495–513

    Article  CAS  PubMed  Google Scholar 

  • Ferraro F, Ma XM, Sobota JA, Eipper BA, Mains RE (2007) Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation. Mol Biol Cell 18:4813–4825

    Article  CAS  PubMed  Google Scholar 

  • González JR, Armengol L, Solé X, Guinó E, Mercader JM, Estivill X, Moreno V (2007) SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23:644–645

    Article  PubMed  Google Scholar 

  • Hauser ER, Crossman DC, Granger CB, Haines JL, Jones CJ, Mooser V, McAdam B, Winkelmann BR, Wiseman AH, Muhlestein JB, Bartel AG, Dennis CA, Dowdy E, Estabrooks S, Eggleston K, Francis S, Roche K, Clevenger PW, Huang L, Pedersen B, Shah S, Schmidt S, Haynes C, West S, Asper D, Booze M, Sharma S, Sundseth S, Middleton L, Roses AD, Hauser MA, Vance JM, Pericak-Vance MA, Kraus WE (2004) A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD study. Am J Hum Genet 75:436–447

    Article  CAS  PubMed  Google Scholar 

  • Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A, Masson G, Gudbjartsson DF, Magnusson KP, Andersen K, Levey AI, Backman VM, Matthiasdottir S, Jonsdottir T, Palsson S, Einarsdottir H, Gunnarsdottir S, Gylfason A, Vaccarino V, Hooper WC, Reilly MP, Granger CB, Austin H, Rader DJ, Shah SH, Quyyumi AA, Gulcher JR, Thorgeirsson G, Thorsteinsdottir U, Kong A, Stefansson K (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491–1493

    Article  CAS  PubMed  Google Scholar 

  • Helgadottir A, Thorleifsson G, Magnusson KP, Grétarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A, Jääskeläinen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsäter A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir E, Walters GB, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J, Niemelä M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G, Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE, Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 40:217–224

    Article  CAS  PubMed  Google Scholar 

  • Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS, Debette S, Lumley T, Folsom AR, van den Herik EG, Bos MJ, Beiser A, Cushman M, Launer LJ, Shahar E, Struchalin M, Du Y, Glazer NL, Rosamond WD, Rivadeneira F, Kelly-Hayes M, Lopez OL, Coresh J, Hofman A, DeCarli C, Heckbert SR, Koudstaal PJ, Yang Q, Smith NL, Kase CS, Rice K, Haritunians T, Roks G, de Kort PLM, Taylor KD, de Lau LM, Oostra BA, Uitterlinden AG, Rotter JI, Boerwinkle E, Psaty BM, Mosley TH, van Duijn CM, Breteler MMB, Longstreth WT, Wolf PA (2009) Genomewide association studies of stroke. N Engl J Med 360:1718–1728

    Article  CAS  PubMed  Google Scholar 

  • Johnson RC, Penzes P, Eipper BA, Mains RE (2000) Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site. J Biol Chem 275:19324–19333

    Article  CAS  PubMed  Google Scholar 

  • Karvanen J, Silander K, Kee F, Tiret L, Salomaa V, Kuulasmaa K, Wiklund PG, Virtamo J, Saarela O, Perret C, Perola M, Peltonen L, Cambien F, Erdmann J, Samani NJ, Schunkert H, Evans A, Project MORGAM (2009) The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts. Genet Epidemiol 33:237–246

    Article  PubMed  Google Scholar 

  • Larson MG, Atwood LD, Benjamin EJ, Cupples LA, D’Agostino RB Sr, Fox CS, Govindaraju DR, Guo CY, Heard-Costa NL, Hwang SJ, Murabito JM, Newton-Cheh C, O’Donnell CJ, Seshadri S, Vasan RS, Wang TJ, Wolf PA, Levy D (2007) Framingham Heart Study 100 K project: genome-wide associations for cardiovascular disease outcomes. BMC Med Genet 8:S5

    Article  PubMed  Google Scholar 

  • Ma XM, Johnson RC, Mains RE, Eipper BA (2001) Expression of kalirin, a neuronal GDP/GTP exchange factor of the trio family, in the central nervous system of the adult rat. J Comp Neurol 429:388–402

    Article  CAS  PubMed  Google Scholar 

  • Matarin M, Brown WM, Singleton A, Hardy JA, Meschia JF, for the ISGS investigators (2008) Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21. Stroke 39:1586–1589

    Article  CAS  PubMed  Google Scholar 

  • McPherson CE, Eipper BA, Mains RE (2002) Genomic organization and differential expression of Kalirin isoforms. Gene 284:41–51

    Article  CAS  PubMed  Google Scholar 

  • McPherson CE, Eipper BA, Mains RE (2004) Kalirin expression is regulated by multiple promoters. J Mol Neurosci 22:51–62

    Article  PubMed  Google Scholar 

  • McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488–1491

    Article  CAS  PubMed  Google Scholar 

  • Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 349:1498–1504

    Article  CAS  PubMed  Google Scholar 

  • O’Donnell CJ, Cupples LA, D’Agostino RB, Fox CS, Hoffmann U, Hwang SJ, Ingellson E, Liu C, Murabito JM, Polak JF, Wolf PA, Demissie S (2007) Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study. BMC Med Genet 8:S4

    Article  PubMed  Google Scholar 

  • Penzes P, Jones KA (2008) Dendritic spine dynamics—a key role for kalirin-7. Trends Neurosci 31:419–427

    Article  CAS  PubMed  Google Scholar 

  • Penzes P, Johnson RC, Alam MR, Kambampati V, Mains RE, Eipper BA (2000) An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction. J Biol Chem 275:6395–6403

    Article  CAS  PubMed  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 81:559–575

    Article  CAS  PubMed  Google Scholar 

  • Rabiner CA, Mains RE, Eipper BA (2005) Kalirin: a dual Rho guanine nucleotide exchange factor that is so much more than the sum of its many parts. Neuroscientist 11:148–160

    Article  CAS  PubMed  Google Scholar 

  • Ratovitski EA, Alam MR, Quick RA, McMillan A, Bao C, Kozlovsky C, Hand TA, Johnson RC, Mains RE, Eipper BA, Lowenstein CJ (1999) Kalirin inhibition of inducible nitric-oxide synthase. J Biol Chem 274:993–999

    Article  CAS  PubMed  Google Scholar 

  • Rudock ME, Ziegler JT, Lehtinen AB, Freedman BI, Carr JJ, Langefeld CD, Bowden DW (2008) Analysis of Kalirin polymorphisms with cardiovascular risk, type 2 diabetes, metabolic syndrome in the Diabetes Heart Study. In: Meeting of the American Society of Human Genetics. Abstract book, abstract 2018, p 388

  • Shah SH, Kraus WE, Crossman DC, Granger CB, Haines JL, Jones CJ, Mooser V, Huang L, Haynes C, Dowdy E, Vega GL, Grundy SM, Vance JM, Hauser ER (2006) Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q. Ann Hum Genet 70:738–748

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Hauser ER, Shah SH, Pericak-Vance MA, Haynes C, Crosslin D, Harris M, Nelson S, Hale AB, Granger CB, Haines JL, Jones CJ, Crossman D, Seo D, Gregory SG, Kraus WE, Goldschmidt-Clermont PJ, Vance JM (2007) Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. Am J Hum Genet 80:650–663

    Article  CAS  PubMed  Google Scholar 

  • Ye S, Willeit J, Kronenberg F, Xu Q, Kiechl S (2008) Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol 52:378–384

    Article  CAS  PubMed  Google Scholar 

  • Youn H, Jeoung M, Koo Y, Ji H, Markesbery WR, Ji I, Ji TH (2007a) Kalirin is under-expressed in Alzheimer’s disease hippocampus. J Alzheimers Dis 11:385–397

    CAS  PubMed  Google Scholar 

  • Youn H, Ji I, Ji HP, Markesbery WR, Ji TH (2007b) Under-expression of Kalirin-7 Increases iNOS activity in cultured cells and correlates to elevated iNOS activity in Alzheimer’s disease hippocampus. J Alzheimers Dis 12:271–281

    CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Tiago Krug, Helena Manso, João Sobral, Joana M. Xavier, Astrid M. Vicente & Sofia A. Oliveira

  2. Instituto de Medicina Molecular, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028, Lisbon, Portugal

    Tiago Krug, Joana M. Xavier & Sofia A. Oliveira

  3. Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

    Helena Manso, João Sobral, Isabel Albergaria, Gisela Gaspar & Astrid M. Vicente

  4. Serviço de Neurologia, Hospital de Santa Maria, Lisbon, Portugal

    Liliana Gouveia & José M. Ferro

  5. Serviço de Neurologia, Hospital Geral de Santo António, Porto, Portugal

    Manuel Correia, Ricardo Taipa & Gabriela Lopes

  6. Serviço de Neurologia, Hospital Garcia de Orta, Almada, Portugal

    Miguel Viana-Baptista

  7. Serviço de Neurologia, Hospital Fernando Fonseca, Amadora, Portugal

    Rita Moiron Simões & Amélia Nogueira Pinto

  8. Serviço de Neurologia, Hospital São Marcos, Braga, Portugal

    Carla Ferreira & João Ramalho Fontes

  9. Serviço de Neurologia, Hospital de São Pedro, Vila Real, Portugal

    Mário Rui Silva & João Paulo Gabriel

  10. Serviço de Neurologia, Hospital Distrital de Mirandela, Mirandela, Portugal

    Ilda Matos

Authors
  1. Tiago Krug
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helena Manso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liliana Gouveia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. João Sobral
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joana M. Xavier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isabel Albergaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gisela Gaspar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Correia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Miguel Viana-Baptista
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rita Moiron Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Amélia Nogueira Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ricardo Taipa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carla Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. João Ramalho Fontes
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mário Rui Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. João Paulo Gabriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ilda Matos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Gabriela Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. José M. Ferro
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Astrid M. Vicente
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Sofia A. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sofia A. Oliveira.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (DOC 58 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krug, T., Manso, H., Gouveia, L. et al. Kalirin: a novel genetic risk factor for ischemic stroke. Hum Genet 127, 513–523 (2010). https://doi.org/10.1007/s00439-010-0790-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-010-0790-y

Keywords

Search

Navigation