Rheumatoid arthritis — susceptible genes
RA is a chronic autoimmune condition that principally attacks joints causing abnormal inflammation. Although its aetiology remains largely unknown, disease frequency suggests the existence of a strong genetic component. Genome-wide association studies have revealed five genetic loci linked to disease development. In addition to these loci, a polymorphism on the gene encoding the immune co-stimulatory molecule CD40 has been recently discovered. Scientists on the EU-funded CD40RA project set out to investigate this further and describe the role of CD40 mutations in RA pathogenesis. Researchers applied next generation sequencing technologies to define the most common CD40 mutations in RA patients. The identified common causal mutations were linked to higher protein expression levels and were subsequently investigated for their biological relevance to disease development. In this context, scientists perturbed the expression of CD40 in B cells to observe a direct correlation with pro-inflammatory signalling. They were also able to identify novel inhibitors of inflammation by screening nearly 2 000 chemical compounds. Additional genes (IL2RA, IL2RB and CD2) identified during the study for increasing the risk of RA extend the list of associated genetic loci. This is expected to help prognosis and improve the prediction of disease severity. At the same time CD40 could serve as a target for the pharmaceutical development of therapeutic drugs.
