Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder typically involving most joints. For a general discussion, see Wikipedia.

Some SNPs may genetically predispose individuals to rheumatoid arthritis, and others may influence response to drugs, such as anti-inflammatories or analgesics, used in the treatment of RA.

Note that several cited papers study a particular form of RA, namely the subgroup of patients with severe rheumatoid arthritis who are characterized by the presence of autoantibodies against cyclic citrullinated peptide (anti-CCP-positive).

SNPs that have been reported to increase risk for RA include:

• Many SNPs in the major histocompatibility complex (MHC) region, most often those tagging the shared epitope (SE) alleles of HLA-DRB1. The risk posed by MHC alleles is the largest of any single region or gene, accounting for ~30% of the heritable risk.

• Two additional SNPs in the MHC region are rs4678 and rs2442728; these appear to be independent of HLA-DRB1.[PMID 19116923]

• A study [PMID 20498205] of 3,000 RA patients from 6 European countries and an accompanying meta-analysis confirmed 18 non-HLA SNPs as associated with RA risk, primarily:
  • rs1160542 (AFF3 gene)
  • rs1678542 (KIF5A)
  • rs2476601 (PTPN22)
  • rs3087243 (CTLA4)
  • rs4810485 (CD40)
  • rs5029937 (6q23)
  • rs10760130 (TRAF1/C5)
  • rs7574865 (STAT4)

• Two SNPs from a ~2,000+ patient study [PMID 17804836]:
  • rs2476601, a SNP in the PTPN22 gene
  • rs3761847, a SNP located in a region containing two genes relevant to chronic inflammation: TRAF1 (tumor necrosis factor receptor–associated factor 1), and C5 (complement component 5).

• From looking just at 40 SNPs in the C5-TRAF1 region in 2,000 patients, a haplotype block of ~65Kb was identified that showed maximal association for one SNP 10.1371/journal.pmed.0040278:
  • rs10818488, a SNP in between the two genes
  • rs1953126, independently identified from this same region

• The 11 SNPs reported in a recent (2007) large study [PMID 17554300]:
  • rs6679677
  • rs6457617
  • rs6684865
  • rs11162922
  • rs3816587
  • rs6920220
  • rs11761231
  • rs2104286
  • rs9550642
  • rs2837960
  • rs743777

• rs2230500, a common missense polymorphism in the PRKCH gene [PMID 17195206]

• rs3087243, a SNP in the CTLA4 gene [PMID 16380915]

• rs2240340, a SNP in the PADI4 gene [PMID 16380915]

• rs3738919, a SNP in the ITGAV gene [PMID 17615072]

• A SNP upstream of the NOS3 gene, apparently lacking an entry in dbSNP [PMID 17009241]

• rs7528684, a SNP in the promoter of the FCRL3 gene, observed in both Japanese and Caucasian populations [PMID 17179172]

• rs2476601, a SNP in the PTPN22 gene, also associated with numerous other autoimmune disorders [PMID 17135225]

• [PMID 17216583] The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells.

• rs3766379 and rs6682654, two CD244 gene SNPs found in Japanese cohorts

• [PMID 17024343] a SNP in the BTLA gene

• rs7574865, a SNP in the third intron of the STAT4 gene [PMID 17804842]

• rs2004640, a SNP in the IRF5 gene [PMID 18843785]

[PMID 17661906] The PTPN22 promoter polymorphism -1123G>C association cannot be distinguished from the 1858C>T association

interesting blog post relating RA to genetics, diet, and infection