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DOI: 10.1160/TH09-11-0787
Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis
Financial support: We acknowledge grants SAF2004–07539, SAF2006–07681 and BFU2007–61699/BFI from the Spanish Ministry of Science and Innovation; PI081420 from the ISCIII, Spanish Ministry of Health and 2002-PIR-00333 from the AGAUR, Generalitat de Catalunya. XM, NG and NS are members of the ISCIII network RTICCC (ISCIII DR06/0020). XM is supported by ISCIII CA06/0200 and B.H. has been recipient (2004–2008) of a grant from the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL06/IDB-001). We also thank the personnel of TIB-MOLBIOL for the design of the LightCycler PCR primers and hybridization probes.
Publikationsverlauf
Received:
20. November 2009
Accepted after major revision:
10. Mai 2010
Publikationsdatum:
23. November 2017 (online)
Summary
Carotid atherosclerosis (CA) is one of the most common causes of stroke, and recent studies suggest that pathways initiated by the interaction of the plasma vitamin K-dependent protein GAS6 with the tyrosine kinase receptors TYRO3, AXL and MERTK (TAM) may have a relevant role in atherogenesis. Furthermore, our previous studies indicated an association between GAS6 and stroke. The aim of this study was to analyse the genetic association between SNPs and haplotypes in GAS6-TAM genes and CA. We performed a case-control study with 233 CA patients confirmed by nuclear magnetic resonance angiography and 202 patients who suffered from cardioembolic (non atherogenic) stroke. For all included subjects information on established risk factors was available. Genotyping of 16 selected tagSNPs was performed by real-time PCR, using either FRET or TaqMan probes. Adjusted logistic regression (LR) analyses indicated that rs2289743 in TYRO3 and rs869016 in MERTK were associated to CA, decreasing its risk (OR [95%CI]=0.39 [0.16–0.94] and OR [95%CI]=0.31 [0.14–0.69], respectively). Linkage disequilibrium results were consistent with the haplotype blocks described in HapMap and adjusted LR analyses revealed that the haplotype ACAA in MERTK, containing the minor allele of the associated SNP, was also associated to CA. No association was observed with GAS6 and AXL variants, which suggests that CA is not the mechanism underlying the reported association between GAS6 and stroke. The association between TYRO3 and MERTK variants and carotid atherosclerosis found in this study reinforces a physiological role of the GAS6-TAM pathway in atherogenesis.
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References
- 1 Manfioletti G, Brancolini C, Avanzi G. et al. The protein encoded by a growth arrest-specific gene (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.
- 2 Angelillo-Scherrer A, de Frutos PG, Aparicio C. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 2001; 7: 215-221.
- 3 Angelillo-Scherrer A, Burnier L, Flores N. et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest 2005; 115: 237-246.
- 4 Bellido-Martin L, García de Frutos P. Vitamin K-dependent actions of Gas6. Vitam Horm 2008; 78: 185-209.
- 5 Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol 2008; 8: 327-336.
- 6 Angelillo-Scherrer A, Burnier L, Lambrechts D. et al. Role of Gas6 in erythropoiesis and anemia in mice. J Clin Invest 2008; 118: 583-596.
- 7 Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006; 129: 1673-1682.
- 8 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.
- 9 Nakano T, Ishimoto Y, Kishino J. et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem 1997; 272: 29411-29414.
- 10 Scott RS, McMahon EJ, Pop SM. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001; 411: 207-211.
- 11 Rothlin CV, Ghosh S, Zuniga EI. et al. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007; 131: 1124-1136.
- 12 Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med 2002; 8: 1249-1256.
- 13 Ross JS, Stagliano NE, Donovan MJ. et al. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann NY Acad Sci 2001; 947: 271-292.
- 14 Muñoz X, Sumoy L, Ramirez-Lorca R. et al. Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Hum Mutat 2004; 23: 506-512.
- 15 Muñoz X, Obach V, Hurtado B. et al. Association of specific haplotypes of GAS6 gene with stroke. Thromb Haemost 2007; 98: 406-412.
- 16 Jiang L, Liu CY, Yang QF. et al. Plasma level of growth arrest-specific 6 (GAS6) protein and genetic variations in the GAS6 gene in patients with acute coronary syndrome. Am J Clin Pathol 2009; 131: 738-743.
- 17 Bamford J, Sandercock P, Dennis M. et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521-1526.
- 18 Barrett JC, Fry B, Maller J. et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265.
- 19 Hurtado B, Abasolo N, Domenech-Santasusana P. et al. Confirmation of inherited protein S deficiency by PROS1 mutational screening: Identification of three novel PROS1 mutations and haplotype analysis of p.Q279X recurrence. Thromb Haemost 2008; 100: 721-724.
- 20 Thorp E, Tabas I. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol 2009; 86: 1089-1095.
- 21 Thorp E, Cui D, Schrijvers DM. et al. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol 2008; 28: 1421-1428.
- 22 Ait-Oufella H, Pouresmail V, Simon T. et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler Thromb Vasc Biol 2008; 28: 1429-1431.
- 23 den Hollander AI, Roepman R, Koenekoop RK. et al. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 2008; 27: 391-419.
- 24 Gal A, Li Y, Thompson DA. et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 2000; 26: 270-271.
- 25 Lemke G, Lu Q. Macrophage regulation by Tyro 3 family receptors. Curr Opin Immunol 2003; 15: 31-36.
- 26 Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyro-sine kinases of the Tyro 3 family. Science 2001; 293: 306-311.
- 27 Seitz HM, Camenisch TD, Lemke G. et al. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol 2007; 178: 5635-5642.
- 28 Niessner A, Weyand CM. Dendritic cells in atherosclerotic disease. Clin Immunol 2009; 134: 25-32.
- 29 Lutgens E, Tjwa M, Garcia de Frutos P. et al. Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis. J Pathol 2008; 216: 55-63.
- 30 Collett G, Wood A, Alexander MY. et al. Receptor tyrosine kinase Axl modulates the osteogenic differentiation of pericytes. Circ Res 2003; 92: 1123-1129.
- 31 Son BK, Akishita M, Iijima K. et al. Mechanism of pi-induced vascular calcification. J Atheroscler Thromb 2008; 15: 63-68.
- 32 de Bakker PI, Yelensky R, Pe’er I. et al. Efficiency and power in genetic association studies. Nat Genet 2005; 37: 1217-1223.
- 33 Balogh I, Hafizi S, Stenhoff J. et al. Analysis of Gas6 in human platelets and plasma. Arterioscler Thromb Vasc Biol 2005; 25: 1280-1286.