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Thromb Haemost 2007; 98(02): 406-412
DOI: 10.1160/TH06-12-0681
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Association of specific haplotypes of GAS6 gene with stroke

Xavier Muñoz   *
1   Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica-IDIBELL, L’Hospitalet de Llobregat, Spain
,
Víctor Obach
2   Stroke Unit, Neurology Service and Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain
,
Begoña Hurtado   *
1   Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica-IDIBELL, L’Hospitalet de Llobregat, Spain
,
Pablo García de Frutos
3   Institute for Biomedical Research of Barcelona, IIBB-CSIC-IDIBAPS, Barcelona, Spain
,
Ángel Chamorro
2   Stroke Unit, Neurology Service and Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain
,
Núria Sala   *
1   Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica-IDIBELL, L’Hospitalet de Llobregat, Spain
› Institutsangaben
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Publikationsverlauf

Received 01. Dezember 2006

Accepted after resubmission 14. Mai 2007

Publikationsdatum:
28. November 2017 (online)

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Summary

The product of the growth arrest-specific gene 6 (GAS6),a ligand for tyrosine kinase receptors, is a vitamin K-dependent protein, structurally related to anticoagulant protein S. Gas6-deficient mice are protected against thrombosis, demonstrating the importance of this protein in the cardiovascular system. In a preliminary study on GAS6 polymorphisms and atherothrombotic disease we found an association between the AA genotype of the c.834+7G>A GAS6 polymorphism and stroke. In order to further explore this association by considering GAS6 haplotypes and the main stroke subtypes,457 patients with ischemic stroke, 199 with hemorrhagic stroke and 150 asymptomatic controls were genotyped for eight GAS6 polymorphisms and other genetic markers in the same genome region. Association was measured by logistic regression analysis.The THESIAS program was used to measure linkage disequilibrium and haplotype frequencies. In univariate analysis, the GAS6 c.834+7AA genotype was found associated with decreased risk for stroke (OR: 0.59; 95%CI: 0.37–0.93).After adjustment for vascular risk factors, association was maintained when stroke subtypes affecting the microvasculature such as lacunar stroke and deep haemorrhage, were grouped together (OR: 0.44; 95%CI: 0.21–0.90). Furthermore, haplotype analysis revealed that association was even stronger when the c.834+7A allele was present in a specific haplotype (CACA) of four GAS6 polymorphisms. From these results we conclude that the A allele of the GAS6 c.834+7G>A polymorphism and more specifically, the CACA haplotype, is less prevalent in patients with stroke, suggesting a protective role for stroke of this haplotype.

Keywords

GAS6 - haplotypes - polymorphisms - stroke

* Present address: Translational Research Laboratory, Institut Català d’Oncologia (ICO)-IDIBELL, l’Hospitalet de Llobregat, Spain.


 

  • References

  • 1 Manfioletti G, Brancolini C, Avanzi G. et al. The protein encoded by a growth arrest-specificgene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993; 13: 4976-4985.
    CrossrefPubMedGoogle Scholar
  • 2 Godowski PJ, Mark MR, Chen J. et al. Reevaluation of the roles of protein S and Gas6 as ligands for there-ceptor tyrosine kinase Rse/Tyro3. Cell 1995; 82: 355-358.
    CrossrefPubMedGoogle Scholar
  • 3 Nagata K, Ohashi K, Nakano T. et al. Identification of the product of growth arrest-specificgene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 1996; 271: 30022-30027.
    CrossrefPubMedGoogle Scholar
  • 4 Bellosta P, Zhang Q, Goff SP. et al. Signaling through the ARK tyrosine kinase receptorprotects from apoptosis in the absence of growth stimulation. Oncogene 1997; 15: 2387-2397.
    CrossrefPubMedGoogle Scholar
  • 5 Collett G, Wood A, Alexander MY. et al. Receptor tyrosine kinase Axl modulates the osteogenic differentiation of pericytes. Circ Res 2003; 92: 1123-1129.
    CrossrefPubMedGoogle Scholar
  • 6 Ishimoto Y, Nakano T. Release of a product of growth arrest-specificgene 6 from rat platelets. FEBS Lett 2000; 466: 197-199.
    CrossrefPubMedGoogle Scholar
  • 7 Melaragno MG, Wuthrich DA, Poppa V. et al. Increased expression of Axl tyrosinekinase after vascular injury and regulation by G protein-coupled receptor agonists in rats. Circ Res 1998; 83: 697-704.
    CrossrefPubMedGoogle Scholar
  • 8 Angelillo-Scherrer A, Garcíade Frutos P, Aparicio C. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 2001; 7: 215-221.
    CrossrefPubMedGoogle Scholar
  • 9 Yanagita M, Ishimoto Y, Arai H. et al. Essential role of Gas6 for glomerular injury in nephrotoxic nephritis. J Clin Invest 2002; 110: 239-246.
    CrossrefPubMedGoogle Scholar
  • 10 Scott RS, McMahon EJ, Pop SM. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001; 411: 207-211.
    CrossrefPubMedGoogle Scholar
  • 11 Melaragno MG, Cavet ME, Yan C. et al. Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt. J Mol Cell Cardiol 2004; 37: 881-887.
    CrossrefPubMedGoogle Scholar
  • 12 Luttun A, Carmeliet P. Genetic studies on the role of proteinases and growth factors in atherosclerosis and aneurysm formation. Ann NY Acad Sci 2001; 947: 124-132 discussion 132-133.
    PubMedGoogle Scholar
  • 13 Grant PJ. The genetics of atherothrombotic disorders: aclinician’s view. J Thromb Haemost 2003; 1: 1381-1390.
    CrossrefPubMedGoogle Scholar
  • 14 Munoz X, Sumoy L, Ramirez-Lorca R. et al. N. Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Hum Mutat 2004; 23: 506-512.
    CrossrefPubMedGoogle Scholar
  • 15 Adams Jr. HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acuteischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
    CrossrefPubMedGoogle Scholar
  • 16 Chamorro A, Revilla M, Obach V. et al. The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis 2005; 19: 91-95.
    CrossrefPubMedGoogle Scholar
  • 17 Chamorro A, Saiz A, Vila N, Ascaso C. et al. Contribution of arterial blood pressure to the clinical expression of lacunar infarction. Stroke 1996; 27: 388-392.
    CrossrefPubMedGoogle Scholar
  • 18 Gilgenkrantz S, Briquel ME, Andre E. et al. Structural genes of coagulation factors VII and X located on 13q34. Ann Genet 1986; 29: 32-35.
    PubMedGoogle Scholar
  • 19 Lichy C, Kropp S, Dong-Si T. et al. A common polymorphism of the protein Z gene is associated with protein Z plasma levels and with risk of cerebral ischemia in the young. Stroke 2004; 35: 40-45.
    PubMedGoogle Scholar
  • 20 Kimura K, Noguchi E, Shibasaki M. et al. Linkage and association of atopic asthma to markers on chromosome 13 in the Japanese population. Hum Mol Genet 1999; 8: 1487-1490.
    CrossrefPubMedGoogle Scholar
  • 21 Zhao JH. 2LD, GENECOUNTING and HAP: Computer programs for linkage disequilibrium analysis. Bioinformatics 2004; 20: 1325-1326.
    CrossrefPubMedGoogle Scholar
  • 22 Obach V, Munoz X, Sala N. et al. Intronic c.573 + 79G>A. Apolymorphism of protein Z gene in haemorrhagic and ischaemic stroke. Thromb Haemost 2006; 95: 1040-1041.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 23 Tanaka A, Ueno Y, Nakayama Y. et al. Small chronic hemorrhages and ischemic lesionsinassociation with spontaneous intracerebral hematomas. Stroke 1999; 30: 1637-1642.
    CrossrefPubMedGoogle Scholar
  • 24 Fazekas F, Kleinert R, Roob G. et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 1999; 20: 637-642.
    PubMedGoogle Scholar
  • 25 Lutgens E, Garciade Frutos P, Aparicio C. et al. Gas6-/-/apoE-/- mice develop a collagen-rich, disorganized plaque phenotype, prone to intraplaque hemorrhage. Circulation 2000; 102 Suppl II 38Abstract.
    PubMedGoogle Scholar
  • 26 Fridell YW, Villa J, Attar EC. et al. GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells. J Biol Chem 1998; 273: 7123-7126.
    CrossrefPubMedGoogle Scholar
  • 27 Korshunov VA, Mohan AM, Georger MA. et al. Axl, areceptor tyrosine kinase, mediates flow-induced vascular remodeling. Circ Res 2006; 98: 1446-1452.
    CrossrefPubMedGoogle Scholar
  • 28 Nakano T, Kawamoto K, Higashino K. et al. Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, gas6. FEBS Lett 1996; 387: 78-80.
    CrossrefPubMedGoogle Scholar
  • 29 Hasanbasic I, Cuerquis J. et al. Intracellular signalling pathways involved in gas6-Axl mediated survival of endothelial cells. Am J Physiol HeartCircPhysiol 2004; 287: H1207-1213.
    PubMedGoogle Scholar
  • 30 Son BK, Kozaki K, Iijima K. et al. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ Res 2006; 98: 1024-1031.
    CrossrefPubMedGoogle Scholar
  • 31 Collett GD, Sage AP, Kirton JP. et al. Axl/phosphatidylinositol 3-kinase signaling inhibits mineral deposition by vascular smooth muscle cells. Circ Res 2007; 100: 502-509.
    CrossrefPubMedGoogle Scholar
  • 32 Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 2006; 99: 1044-1059.
    CrossrefPubMedGoogle Scholar
  • 33 Yin J, McLachlan C, Chaufour X. et al. Growth arrest-specific gene 6 expression in proliferating rabbit vascular smooth muscle cells in vitro and in vivo. Electrophoresis 2000; 21: 3851-3856.
    CrossrefPubMedGoogle Scholar
  • 34 Borgel D, Clauser S, Bornstain C. et al. Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis. Crit Care Med 2006; 34: 219-222.
    CrossrefPubMedGoogle Scholar
  • 35 Gibot S, Massin F, Cravoisy A. et al. Growth arrest-specific protein 6 plasma concentrations during septic shock. Crit Care 2007; 11: R8.
    CrossrefPubMedGoogle Scholar
  • 36 Balogh I, Hafizi S, Stenhoff J. et al. Analysis of Gas6 in human platelets and plasma. Arterioscler Thromb Vasc Biol 2005; 25: 1280-1286.
    CrossrefPubMedGoogle Scholar