CD40RA

Identification of functional common and rare variants in the CD40 signaling pathway in Rheumatoid Arthritis

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Rheumatoid Arthritis is a common chronic autoimmune disease that affects approximately 1% of the adult population worldwide.Although its causes are largely unknown, it is clear that there is a considerable heritable component. In 2007, three genome-wide association studies (GWAS) as well as candidate gene approaches successfully increased the number of RA gene loci from two to five. More recently, a meta-analysis of these GWAS has been completed (Nature Genetics, in press). The most significant finding outside of the known RA risk loci was of a common polymorphism near the CD40 gene (odds ratio = 0.87, p = 5.1 x 10-9). While this represents a true disease gene, several questions remain to be answered to fully comprehend the role of CD40 mutations in RA pathogenesis. While this study provides direct evidence that CD40 is critical in RA pathogenesis, at least three crucial questions remain: 1) what is the exact common causal mutation? 2) Are there rare mutations that contribute to disease not accounted for in the genome-wide studies as they are designed to identify common mutations? 3) What is the biological relevance of both types of CD40 mutations? My proposed research will address these three critical questions by applying next generation genetic technologies (e.g., high-throughput Solexa sequencing) in large RA case-control collections available in the Plenge laboratory at Harvard Medical School (Outgoing Host Institute), together with functional immunology available in the Huizinga laboratory at Leiden University Medical Center (Return Host Institute). To achieve my goals, genetic and immunological resources will be combined to identify, validate and functionally characterise both common and rare functional mutations involved in the establishment of RA. This comprehensive approach will generate insight into a pathway relevant to disease development.'

Introduzione (Teaser)

One in a hundred people worldwide suffer from rheumatoid arthritis (RA). European scientists decided to investigate the genetic susceptibility to the disease with particular focus on CD40.

Descrizione progetto (Article)

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.