Rs4810485

rs4810485 is a SNP associated with rheumatoid arthritis (RA), a chronic autoimmune disease characterized by joint inflammation. At this locus, the minor allele, T, protects against RA. The SNP is located on chromosome 20q13 in the second intron of the CD40 gene, which encodes a receptor that is expressed on the surface of multiple immune cells. CD40 binds the ligand CD154 which is expressed by activated T cells, and this interaction plays a critical role in T cell helper activity in the immune system. rs4810495 is closely linked with another SNP, rs1883832, that appears to lesson translation of the CD40 gene, affecting this critical signaling pathway that leads to B cell proliferation. Mouse model knockouts of CD40 have been shown to alleviate arthritis.

The association between rs4810485 and RA was first identified through a genome-wide association study (GWAS) meta-analysis and two subsequent replication studies in patients with European ancestry. This study looked at the major allele G versus the minor allele T in a meta-analysis of previous GWAS followed by two replication studies. In the GWAS meta-analysis, which had 3,393 cases and 12,460 controls, they found rs4810485 to be associated with RA with a p-value of 2.4x10-7 and an odds ratio of 0.83. Two replication studies looking at 31 loci in combined 3,929 cases and 5,807 controls found the position to be associated with the disease with a p-value of 0.0032 and an odds ratio of 0.91. Jointly, the meta-analysis and replication studies showed an association with a p-value of 8.2x10-9 surpassing a conservative level of significance for joint analysis and an odds ratio of 0.87, suggesting that the minor allele T gives a modest protective effect against RA.

The association with RA was confirmed in a targeted validation study in the United Kingdom with 3,962 cases and 3,531 control patients. This study found rs4810485 to be associated with RA with a p-value of 2x10-4 and an odds ratio of 0.86. Since this was a targeted study looking at 4 specific loci, the p-value is significant. Again, the odds ratio suggests a modest protective affect for the minor allele T.

An additional study looked at this SNP and its association with RA in individuals of Korean ancestry. This study found no association between rs4810485 and RA in patients with Korean ancestry. The targeted validation study looked at 5 SNPs associated with RA in Europeans in 1,113 Korean cases and 988 controls, and found a p-value of 0.39 and an odds ratio of 1.06, suggesting no association between the SNP and RA in Koreans. This case highlights the importance of accounting for ancestry when testing genome-wide associations.