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Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.

Recarte-Pelz P, Tàssies D, Espinosa G, Hurtado B, Sala N, Cervera R, Reverter JC, de Frutos PG - Arthritis Res. Ther. (2013)

Bottom Line: Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded.We show here that this correlation is affected by common polymorphisms in the genes of the system.These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population.

Methods: Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples.

Results: Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients.

Conclusions: The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

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Plasma concentrations of sMerTK, sAxl and growth arrest-specific gene 6 protein (GAS6) according to specific genotypes. Genotypes giving significant differences in the concentration of their gene products are selected. (A) GAS6 rs8191974 (intron 8, c.834 ± 7G > A); (B) MERTK rs869016 (intron 1a, c.61 ± 2737G > A) and (C), AXL rs2304232 (intron 6 c.2169 ± 9A > G). SLE, systemic lupus erythematosus.
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Figure 3: Plasma concentrations of sMerTK, sAxl and growth arrest-specific gene 6 protein (GAS6) according to specific genotypes. Genotypes giving significant differences in the concentration of their gene products are selected. (A) GAS6 rs8191974 (intron 8, c.834 ± 7G > A); (B) MERTK rs869016 (intron 1a, c.61 ± 2737G > A) and (C), AXL rs2304232 (intron 6 c.2169 ± 9A > G). SLE, systemic lupus erythematosus.

Mentions: Next, we genotyped SNPs of the GAS6/ProS-TAM genes selected from a previously described population of patients with atherosclerotic disease and controls in the same geographical area [23,24]. From those determined, three SNPs showed clear differences among genotypes in their gene product plasma concentrations. For SNP rs869016 in MERTK intron 1 (c.61 ± 2737G > A), most of the difference in sMerTK concentration could be attributed to the AA group. The concentration of sMerTK increased from 12.3 ± 1.8 ng/mL in five AA controls to 29.3 ± 5.5 ng/mL in the eight AA homozygote patients. This concentration was significantly higher compared to the AG and GG patients (P = 0.019). Genotypes carrying the A allele of GAS6 intron 8 SNP variant (rs8191974) increased from 26.2 ± 1.3 ng/mL in 33 AA ± AG controls compared to 33.1 ± 1.8 ng/mL in 31 SLE patients (P = 0.002), while there was no difference in the GG group (Figure 3). In the case of AXL, the observed increase in sAxl could be attributed to carriers of the G allele (24.6 ± 5.2 ng/mL in 17 GG ± AG controls compared to 41.2 ± 3.8 ng/mL in 19 AG SLE patients), while no differences were observed in the AA genotype between SLE and controls. No differences in plasma concentrations were observed in relation to the other SNPs genotyped.


Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.

Recarte-Pelz P, Tàssies D, Espinosa G, Hurtado B, Sala N, Cervera R, Reverter JC, de Frutos PG - Arthritis Res. Ther. (2013)

Plasma concentrations of sMerTK, sAxl and growth arrest-specific gene 6 protein (GAS6) according to specific genotypes. Genotypes giving significant differences in the concentration of their gene products are selected. (A) GAS6 rs8191974 (intron 8, c.834 ± 7G > A); (B) MERTK rs869016 (intron 1a, c.61 ± 2737G > A) and (C), AXL rs2304232 (intron 6 c.2169 ± 9A > G). SLE, systemic lupus erythematosus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672795&req=5

Figure 3: Plasma concentrations of sMerTK, sAxl and growth arrest-specific gene 6 protein (GAS6) according to specific genotypes. Genotypes giving significant differences in the concentration of their gene products are selected. (A) GAS6 rs8191974 (intron 8, c.834 ± 7G > A); (B) MERTK rs869016 (intron 1a, c.61 ± 2737G > A) and (C), AXL rs2304232 (intron 6 c.2169 ± 9A > G). SLE, systemic lupus erythematosus.
Mentions: Next, we genotyped SNPs of the GAS6/ProS-TAM genes selected from a previously described population of patients with atherosclerotic disease and controls in the same geographical area [23,24]. From those determined, three SNPs showed clear differences among genotypes in their gene product plasma concentrations. For SNP rs869016 in MERTK intron 1 (c.61 ± 2737G > A), most of the difference in sMerTK concentration could be attributed to the AA group. The concentration of sMerTK increased from 12.3 ± 1.8 ng/mL in five AA controls to 29.3 ± 5.5 ng/mL in the eight AA homozygote patients. This concentration was significantly higher compared to the AG and GG patients (P = 0.019). Genotypes carrying the A allele of GAS6 intron 8 SNP variant (rs8191974) increased from 26.2 ± 1.3 ng/mL in 33 AA ± AG controls compared to 33.1 ± 1.8 ng/mL in 31 SLE patients (P = 0.002), while there was no difference in the GG group (Figure 3). In the case of AXL, the observed increase in sAxl could be attributed to carriers of the G allele (24.6 ± 5.2 ng/mL in 17 GG ± AG controls compared to 41.2 ± 3.8 ng/mL in 19 AG SLE patients), while no differences were observed in the AA genotype between SLE and controls. No differences in plasma concentrations were observed in relation to the other SNPs genotyped.

Bottom Line: Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded.We show here that this correlation is affected by common polymorphisms in the genes of the system.These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population.

Methods: Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples.

Results: Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients.

Conclusions: The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

Show MeSH
Related in: MedlinePlus