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Recarte-Pelz P.,Institute of Biomedical Research of Barcelona IIBB CSIC IDIBAPS | Tassies D.,University of Barcelona | Espinosa G.,Institute Clinic Of Medicina I Dermatologia | Hurtado B.,Institute of Biomedical Research of Barcelona IIBB CSIC IDIBAPS | And 4 more authors.
Arthritis Research and Therapy

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. © 2013 Recarte-Pelz et al.; licensee BioMed Central Ltd. Source

Marin F.,Institute Catala dOncologia IDIBELL ICO | Bonet C.,Institute Catala dOncologia IDIBELL ICO | Munoz X.,Institute Catala dOncologia IDIBELL ICO | Garcia N.,Institute Catala dOncologia IDIBELL ICO | And 7 more authors.

In order to assess whether inherited genetic variability in the mucin genes associates with the evolution of gastric cancer precursor lesions (GCPLs), we genotyped 22 tagSNPs in MUC1, MUC6 and MUC2 genes of 387 patients with GCPLs that had been followed up for 12.8 years. According to the diagnosis at recruitment and at the end of follow-up, the lesions did not change in 43.1% of the patients, regressed in 28.7% and progressed in 28.2%. Three SNPs in the 3'-moiety of MUC2 were significantly associated with a decreased risk of progression of the lesions, whereas another four SNPs, located at the 5'-moiety, were found to be significantly associated either with increased [one single-nucleotide polymorphism (SNP)] or decreased (three SNPs) probability of regression. Stratified analysis indicated that significance was maintained only in those subjects positive for Helicobacter pylori infection and in those not consuming non-steroidal anti-inflammatory drugs, which were found protective against lesion progression. Haplotype analyses indicated the presence of two haplotypes, one in each moiety of the gene, that were significantly associated with decreased risk of progression of the lesions [odds ratio (OR) = 0.49 and 0.46; 95% confidence interval (CI) = 0.28-0.85 and 0.25-0.86, respectively]. The 5'-end haplotype was also associated with increased probability of regression (OR = 1.67; 95% CI = 1.02-2.73), altogether suggesting a protective role against progression of the precancerous lesions. No significant association was found with variants in MUC1 and MUC6 genes. These results indicate, for the first time, that genetic variability in MUC2 is associated with evolution of GCPLs, especially in H. pylori infected patients, suggesting a role of this secreted mucin in gastric carcinogenesis. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

Marin F.,Institute Catala Doncologia Ico Idibell | Marin F.,Institute Catala dOncologia IDIBELL ICO | Garcia N.,Institute Catala Doncologia Ico Idibell | Garcia N.,Institute Catala dOncologia IDIBELL ICO | And 7 more authors.
Journal of Molecular Diagnostics

Due to their ability to metabolize xenobiotics, glutathione S-transferases (GSTs) play an important role in cellular protection. GST family members μ(GSTM1) and θ (GSTT1) exhibit a common polymorphism that results in the complete deletion of the gene (null allele). Homozygous deletions, which result in the absence of the enzyme, are considered a risk factor for several diseases, including cancer. We report a simple, low cost, and high throughput assay for the simultaneous analysis of the GSTM1 and GSTT1 null polymorphisms in a single step. The assay is based on multiplex real-time PCR in the presence of SYBR Green I and genotype discrimination by melting curve analysis in a LightCycler. We have genotyped 792 samples to compare this new approach with conventional PCR followed by gel electrophoresis. Comparison of the methods gave a good agreement, with κ values of 0.88 for GSTM1 and 0.64 for GSTT1. Reanalysis of discrepant samples indicated that absence of amplification of the larger GSTT1 fragment by conventional PCR accounted for most of the discrepancies. Moreover, the improved amplification efficiency of the real-time PCR results in a significant reduction of missing values. Due to its simplicity and low cost, this assay is well suited for the rapid analysis of GST-null genotypes in studies that involve large number of samples. Copyright © American Society for Investigative Pathology. Source

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