Six new rheumatoid arthritis (RA) risk loci have been identified from a meta-analysis of single nucleotide polymorphisms (SNPs) in European populations, researchers report.
Robert Plenge (Harvard Medical School, Boston, Massachusetts, USA) and colleagues conducted a meta-analysis of two published genome-wide association studies totaling 3393 autoantibody-positive RA cases and 12,462 controls to identify RA risk loci in European populations.
The team initially investigated 340,000 previously genotyped SNPs and used statistical testing to determine their association with RA risk. The 31 top-ranked SNPs that were not previously associated with RA were then genotyped.
One variant, rs4810485, in the CD40 gene locus had a high level of significance and thus represents a confirmed RA risk. The CD40 protein is expressed on the surface of multiple immune cells and plays an important role in provision of helper activity by CD4+ T cells in immune reactions.
“These associations provide strong evidence for the importance of the CD40 signaling pathway in autoantibody-positive RA,” write Plenge and co-authors in the journal Nature Genetics.
The researchers also identified an association at the CCL21 gene locus, which encodes a protein involved in lymphocyte trafficking and has previously been implicated in the organization of lymphoid tissue affected by RA.
In addition, evidence of association at four more gene loci was revealed: MMEL1-TNFRSF14, which is a member of the TNF-receptor super-family; CDK6, a cyclin-dependant kinase and key mediator B cell proliferation; PRKCQ, which encodes a kinase required for the activation of the transcription factor NF-κB; and KIF5A-PIP4K2C, which has been implicated in signaling through the B cell receptor.
The authors conclude: “Our study has identified a RA–associated variant for European populations at the CD40 locus, provided strong evidence for association at the CCL21 locus, and also suggests association at four other loci. It also provides empirical data suggesting that additional common alleles with odds ratios ~1.15 remain to be discovered.”