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).

As of late 2013, the most comprehensive model predicting risk for rheumatoid arthritis, taking into account all 46 known RA-associated genetic loci, has at best "modest" success, and it was deemed by it's creators as deemed "insufficiently accurate for general population screening".[PMID 24092415] Just after that, in early 2014 another 42 RA-associated SNPs were published based on a meta-analysis of 30,000 RA patients, apparently bringing the total number to 101. However, no modeling was performed so it's unknown if these additional SNPs have brought screening any closer or even made overall RA risk estimates more accurate. [PMID 24390342]

Relevant genes

List of relevant genes associated with RA can be found from the NIH Genetics Home Reference Rheumatoid Arthritis Related genes page.

• AFF3
• ARID5B
• BLK
• C5
• CCL21
• CCR6
• CD2
• CD28
• CD40
• CD5
• CD58
• CTLA4
• FCGR2A
• FCGR2B
• GATA3
• HLA-B
• HLA-DPB1
• HLA-DRB1
• IKZF3
• IL2
• IL21
• IL2RA
• IL2RB
• IL6R
• IL6ST
• IRAK1
• IRF5
• IRF8
• KIF5A
• PADI4
• PIP4K2C
• POU3F1
• PRDM1
• PRKCQ
• PTPN22
• PTPRC
• PXK
• RASGRP1
• RBPJ
• RCAN1
• REL
• RUNX1
• SPRED2
• STAT4
• TAGAP
• TLE3
• TNFAIP3
• TNFRSF14
• TRAF1
• TRAF6
• TYK2

Some relevant SNPs

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

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

• [PMID 20498205] A study 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)
  • rs7574865 (STAT4)
  • rs10760130 (TRAF1/C5)

• [PMID 20437071] Two CD244 gene SNPs found in Japanese cohorts:
  • rs3766379
  • rs6682654

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

• [PMID 17880261]. 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 Note: the correction of the article 10.1371/journal.pmed.0040358.
  • rs1953126, independently identified from this same region
  • rs10818488, a SNP in between the two genes

• [PMID 17804836] Two SNPs from a ~2,000+ patient study:
  • 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).´

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

• [PMID 16380915] two SNPs in the PADI4 gene
  • rs2240340
  • rs3087243

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

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

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

• 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]

• 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

• [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.

• [PMID 17024343] a SNP in the BTLA gene

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

Links

NIH Genetics Home Reference page Rheumatoid arthritis. Interesting blog post relating RA to genetics, diet, and infection.