Estudio de factores genéticos relacionados con la susceptiblidad a padecer artritis reumatoide y con la variabilidad interindividual en la respuesta al tratamiento con infliximab

Résumé

ABSTRACT: Objectives: Study polymorphisms in genes related to activation of apoptosis by the extrinsic pathway to: 1. Assess, through a genetic susceptibility study, the influence of polymorphisms in genes encoding TRAILR1, TRAIL, FAS and FASL in the risk of rheumatoid arthritis (RA). 2. Study, through a pharmacogenetic study, the influence of polymorphisms in genes encoding TRAILR1, TRAIL, FAS and FASL in the response to infliximab at three, six and twelve months from the start of treatment. 3. Evaluate, through a haplotype study, whether the combination of the polymorphisms studied is associated with RA susceptibility or with response to treatment with infliximab at three, six and twelve months from the start of treatment. Polymorphisms under study are TRAILR1: rs20576 and rs2230229 in TRAIL: rs12488654, in FAS: rs1800682 and FASL: rs763110. Material and methods: Patients included in the study come from the Department of Rheumatology at the University Hospital Santa María del Rosell de Cartagena (HUSMR). The study period was between February 2007 and February 2010. 90 patients diagnosed with RA were included in genetic susceptibility study, which were compared with a group of 151 healthy controls. 43 patients diagnosed of RA and treated with infliximab were included in the pharmacogenetic study of response to treatment. Assessment of response was made according to response criteria established by the EULAR (European League Against Rheumatism). These criteria are based on the calculation of the DAS-28 index (Disease Activity Score 28). The DAS-28 includes the assessment of pain and inflammation in 28 joints and also considered the ESR (erythrocyte sedimentation rate) and the global disease assessment. This index takes into account the degree of improvement and the current situation of the patient. According to EULAR criteria of response to treatment it can be classified as good, moderate or absent. Patients were classified as responders and no responders. Detection of polymorphisms was performed through a competitive allele-specific PCR (KASPar) using the FRET technology for detection of genotypes. For both studies, statistical analysis was performed using 3.1 Epidat and SHEsis software. The genotype distributions were consistent with the Hardy-Weinberg equilibrium (p>0.5) Pearson ?2 test was used for the statistical analysis (p<0.05 was considered as statistically significant). Conclusions 1. Studied polymorphisms have shown no association with susceptibility to RA. 2. There has been a trend towards significance in the association of the T allele at rs1800682 (FAS) with RA risk. 3. Haplotypes including T and C alleles in rs1800682 (FAS) and rs763110 (FASL) and the A allele in rs2230229 and rs20576 (TRAILR1) are associated with a higher RA risk. 4. Studied polymorphisms showed no significant association with response to infliximab at three, six and twelve months from the start of treatment. 5. Haplotype including the combination of alleles TT at rs1800682 (FAS) and rs763110 (FASL) with AG combination alleles in rs2230229 (TRAILR1) and rs12488654 (TRAIL) is associated with a poorer response to treatment with infliximab at three months of onset. 6. Combination polymorphisms in the extrinsic apoptosis related genes seem to contribute in response to infliximab and could be useful in the clinical management of RA patients treated with this monoclonal antibody.