Search

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.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment among people over 50 years of age, accounting for up to 50% of all cases of legal blindness in Western countries. Although the aging represents the main determinant of AMD, it must be considered a multifaceted disease caused by interactions among environmental risk factors and genetic backgrounds. Mounting evidence and/or arguments document the crucial role of inflammation and immune-mediated processes in the pathogenesis of AMD. Proinflammatory effects secondary to chronic inflammation (e.g., alternative complement activation) and heterogeneous types of oxidative stress (e.g., impaired cholesterol homeostasis) can result in degenerative damages at the level of crucial macular structures, that is photoreceptors, retinal pigment epithelium, and Bruch’s membrane. In the most recent years, the association of AMD with genes, directly or indirectly, involved in immunoinflammatory pathways is increasingly becoming an essential core for AMD knowledge. Starting from the key basic-research notions detectable at the root of AMD pathogenesis, the present up-to-date paper reviews the best-known and/or the most attractive genetic findings linked to the mechanisms of inflammation of this complex disease.