GENETICA E FARMACOGENETICA DELL’ARTRITE REUMATOIDE: RICERCA DI VARIANTI ASSOCIATE ALL’OCCORRENZA DI MALATTIA O ALLA RISPOSTA FARMACOLOGICA

Rheumatoid Arthritis (RA) is considered the most common autoimmune disease, affecting the 0.5-1% of the population. It consists in a chronic widespread inflammation that affects mainly synovial tissues, leading to a slow and progressive joint destruction and consequent loss of functionality. This pathology may involve also other tissues and it is often related to reduction in life quality and, in the most serious cases, to increased mortality. The etiological causes are still unknown. RA mainly affects women, with a females:males ratio of 3:1. There are various (genetic and environmental) risk factors that, through alteration of immune and inflammation mechanisms, lead to disease development, thus defining RA a multifactorial condition. Recent 'Genome-wide' association studies (GWAS) led to the identification of several genetic variations associated to susceptibility for RA development or to response to the main drugs used for treatment, underling important differences between populations. On the basis of this scientific evidence, we conducted an experimental study aimed to recognise genetic polymorphisms associated to RA development risk in the Italian population, and to identify variants predicting the response to pharmacological treatments with conventional and new generation drugs. We evaluated a panel of polymorphic variants in genes involved in folates transport and metabolism, as folates are direct targets of methotrexate, the most used drug in RA treatment that acts as folate antagonist. The analysis carried out showed that some of these polymorphisms significantly influence RA occurrence risk and treatment response, both in terms of efficacy and toxicity. Using 'data mining' applications, eventual genetic synergies or redundancies were investigated in order to detect functional interactions between folates metabolism and transport components. Moreover, we investigated genetic variants in HLA region, which is considered responsible for the major genetic contribute in terms of disease susceptibility. In this field, we studied the function of several polymorphic variants associated to the gene HLA-DRB1 and their influence in determine RA treatments response. The variants associated to this locus indicated a trend of susceptibility to RA; in particular, one of these variants seemed to influence the efficacy response to the biological drugs. Studies related to functional variants within HLA-G gene, a regulator of immunosuppression response and related to immune-mediated disease, confirmed the association between the rs16375 variant and RA occurrence risks in Italian population, showing that the association is specific for only females. Results from this study provide important genetic information on RA pathogenesis, which could eventually be applied for personalization of medical treatments. Such approaches could be applied both at early-diagnostic level, for identification of pre-clinical cases, and for choosing of most efficient therapy according to RA patients genetic profiles, therefore reducing the risks of adverse events and with important implications also in terms of health economy.