The genes behind arthritis

Through genome-wide association studies, scientists identified regions in the genome that increase predisposition to RA but not the actual genes responsible. This is due to the complexity of associating genotype to phenotype in RA and other autoimmune conditions.

Tumour necrosis factor alpha-induced protein 3 (TNFAIP3) negatively regulates NF-kappaB and helps inhibit TNF-receptor–mediated signalling effects. Intergenic region (IGR) refers to DNA sequences located between genes. The IGR upstream TNFAIP3 was linked to autoimmune conditions such as RA, type 1 diabetes, inflammatory bowel disease and systemic lupus erythematosus.

The GENTOPHEN project focused on identifying the variants in the TNFAIP3 locus that increases susceptibility to RA. Researchers employed cutting edge techniques including bioinformatics, electrophoretic mobility shift assays, chromatin immunoprecipitation and a modified version of the chromosome conformation capture technique for this purpose.

Results revealed that the gene variant rs6927172 in the TNFAIP3 loci is implicated in impaired regulation of TNFAIP3 expression. This suggests that there is a high likelihood that rs6927172 contributes to RA pathogenesis.

Project activities led to the development of techniques that transcend the current state of the art in the field of complex disease genetics. These techniques could help elucidate the underlying aetiology of other complex diseases besides RA.