Human vitamin K-dependentGAS6: Gene structure, allelic variation, and association with stroke

Abstract

The product of the growth arrest-specific gene 6 (GAS6), a ligand for the Axl, Sky, and Mer 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. The present study was aimed at determining the human GAS6 intron-exon structure and analyzing the gene for the presence of allelic variants that could be associated with atherothrombotic disease. Online analyses allowed us to localize 15 GAS6 exons and to determine the sequence of their intron-flanking regions, in a chromosome 13 region spanning 43.8 kb of DNA. SSCP analysis of PCR-amplified GAS6 exons with their intron-flanking regions from a minimum of 12 control DNA samples, revealed the presence of eight different variants, which were confirmed to be single nucleotide polymorphisms (SNPs). Three of them (c.1263G>C, c.1332C>T, and c.1869T>C) are localized in exons 11, 12, and 14, and appear to be neutral since they do not modify the encoded amino acid. The other SNPs (c.280+170C>G, c.712+26G>A, c.713-155C>T, c.834+7G>A, and c.1478-94C>G) are in introns 3, 7, 8, and 12. A preliminary analysis of five of these SNPs in a group of 110 healthy controls and 188 patients with atherothrombotic disease has revealed statistically significant differences between controls and stroke patients in the allelic distributions of one of these variants (c.834+7G>A in intron 8). The SNP identification in GAS6 reported here would be very useful in future association studies aimed at determining the physiologic role of GAS6 in stroke and other human diseases.

Development of a Novel Immunoassay for the Assessment of Plasma Gas6 Concentrations and Their Variation with Hormonal Status

“…Because vessel wall response to injury is a major component of human atherothrombotic pathology, Gas6 could be a key player in the pathophysiology of cardiovascular diseases. Consistent with this theory, Munoz et al (8 ) have shown that a polymorphism of the GAS6 gene was associated with stroke. Therefore, lower plasma Gas6 concentrations could result in higher sensitivity to vascular injury, with plaque fibrous cap thinning, vascular smooth muscle cell and endothelium apoptosis; and, thus, a higher susceptibility to plaque rupture or erosion.…”

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

“…54 Still, Gas6 levels in plasma were higher in patients with venous thromboembolic disease as compared with healthy volunteers. 55 Also, genetic evidence shows an association between certain single nucleotide polymorphisms in the GAS6 gene and stroke, 56 making involvement of TAM receptor in human, and not only murine, hemostasis likely.…”

Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

“…Conversely, abnormal activation of the Gas6 pathway might also contribute to disease phenotypes due to platelet activation (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome) that are characterized by thrombosis. A very recent study indicates a significant association between a Gas6 polymorphism and ischemic stroke, placing Gas6 as a promising candidate for a susceptibility gene for this disease (45).…”