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Thromb Haemost 2010; 104(03): 592-598
DOI: 10.1160/TH09-11-0787
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis

Begoña Hurtado
1   Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
5   Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona (IIBB-CSIC-IDIBAPS), Barcelona, Spain
,
Nerea Abasolo
1   Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
,
Xavier Muñoz
1   Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
,
Nadia García
1   Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
,
Yolanda Benavente
2   Unit of Infections and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
3   CIBERESP, L’Hospitalet de Llobregat, Spain
,
Francisco Rubio
4   Neurology Service, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
,
Pablo García de Frutos
5   Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona (IIBB-CSIC-IDIBAPS), Barcelona, Spain
,
Jerzy Krupinski
6   Department of Neurology, Stroke Unit, Hospital Universitari Mutua de Terrassa, Terrassa, Spain; Cardiovascular Research Center, ICCC, Barcelona, Spain
7   Fundacio IDIBELL, Barcelona, Spain
8   School of Biology, Chemistry and Health Science, and Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
,
Núria Sala
1   Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
› Author Affiliations 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.
Further Information

Publication History

Received: 20 November 2009

Accepted after major revision: 10 May 2010

Publication Date:
23 November 2017 (online)

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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.

Keywords

GAS6 - TAM receptors - atherosclerosis - polymorphisms - genetic susceptibility

 

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