Análisis de la longitud de los telómeros y biomarcadores epigenéticos de la edad en pacientes con artrosis o con artritis reumatoide

La artrosis y la artritis reumatoide (AR) son enfermedades reumáticas crónicas, que causan dolor articular y périda de la movilidad. El envejecimiento es un factor de riesgo en ambas patologías, si bien los mecanismos de su implicación todavía no están esclarecidos. En los últimos años se han desarrollado nuevos biomarcadores de edad basados en cambios en la metilación que permiten estimar la edad biológica mediante el análisis de muestras de ADN. Mediante el análisis de la metilación en 8 sitios CpG, se ha estimado la edad biológica muestras de sangre, de hueso y de cartílago de pacientes y controles con artrosis. Se ha observado un envejecimiento específico en el cartílago como tejido principalmente afectado por la enfermedad. Para confirmar los resultados negativos encontrados en el análisis de sangre completa, se ha realizado una determinación de la longitud de los telómeros que confirman la ausencia de envejecimiento prematuro en las mismas. También se ha determinado la edad biológica de pacientes con artritis reumatoide y controles en muestras de sangre, mediante el análisis de la metilación y de la longitud de los telómeros. Se puede concluir que los pacientes con artritis reumatoide no presentan un envejecimiento prematuro biológicamente relevante

Replication Study Of Polymorphisms Associated With Response To Methotrexate In Patients With Rheumatoid Arthritis

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as.DAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to.DAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response

Simplified Assay for Epigenetic Age Estimation in Whole Blood of Adults

Biological age is not always concordant with chronological age and the departures are of interest for understanding how diseases and environmental insults affect tissue function, organismal health, and life expectancy. The best-known biological age biomarker is telomere length, but there are more accurate biomarkers as the recently developed based in epigenetic, transcriptomic, or biochemical changes. The most accurate are the epigenetic biomarkers based on specific changes in DNA methylation referred as DNA methylation age measures (DmAM). Here, we have developed and validated a new DmAM that addresses some limitations of the previously available. The new DmAM includes the study in whole blood (WB) of 8 CpG sites selected as the most informative on a training set of 390 healthy subjects. The 8 CpG DmAM showed better accuracy than other DmAM based in few CpG in an independent validation set of 335 subjects. Results were not significantly influenced by sex, smoking, or variation in blood cell subpopulations. In addition, the new 8 CpG DmAM was amenable to study in a single multiplex reaction done with methylation-sensitive single-nucleotide primer extension (MS-SNuPE), a methodology based on commercially available reagents and run in capillary electrophoresis sequencers. In this way, the high cost of DNA methylation microarrays or of a pyrosequencer, which are needed for alternative DmAM, was avoided. Performance of the DmAM with MS-SNuPE was assessed in a set of 557 donors, showing high call rate (>97%), low CV (<3.3%) and high accuracy (Mean Absolute Deviation = 6.07 years). Therefore, the 8 CpG DmAM is a feasible and accurate tool for assessing the epigenetic component of biological age in blood of adults

Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients

<div><p>Patients with rheumatoid arthritis (RA) have an increased mortality rate that is associated with the presence of RA-specific autoantibodies in many studies. However, the relative role of rheumatoid factor (RF), anti-CCP antibodies and the most recently established RA-autoantibodies, directed against carbamylated proteins (anti-CarP antibodies), is unclear. Here, we have assessed the role of these three antibodies in 331 patients with established RA recruited from 2001 to 2009 and followed until November 2015. During this time, 124 patients died (37.5%). This death rate corresponds to a mortality rate 1.53 (95% CI 1.26 to 1.80) folds the observed in the reference population. We used for analysis of all-cause mortality the Cox proportional hazard regression model with adjustment for age, sex and smoking. It showed a trend for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 1.79), but only the HR of the anti-CarP antibodies was significant (HR = 1.79, 95% CI 1.23 to 2.61, p = 0.002). In addition, the multivariate analysis that included all autoantibodies showed a marked decrease in the HR of RF and of anti-CCP antibodies, whereas the HR of anti-CarP remained significant. This increase was specific of respiratory system causes of death (HR = 3.19, 95% CI 1.52 to 6.69, p = 0.002). Therefore, our results suggest a specific relation of anti-CarP antibodies with the increased mortality in RA, and drive attention to their possible connection with respiratory diseases.</p></div

Conditional analysis of the HR observed with the number of autoantibodies.

<p>The HR for the number of antibodies (# Ab) obtained in Cox proportional analysis was considered either on itself (to the left of the dotted vertical line) or conditional on the presence of each of the three specific autoantibodies (to the right of the dotted vertical line). The asterisks, *, denote significantly increased HR.</p

Distribution of patients with RA positive for the different autoantibodies.

<p>A proportional Venn diagram representing percentages (%) of patients in each of the antibody strata: anti-CCP positive in the lower left oval, RF positive in the lower right oval and anti-CarP positive in the upper one. Percentage of triple negatives is shown outside the Venn diagram in the upper left corner.</p