Genetics of Rheumatic Disease

Alex Clarke; Timothy J Vyse


Arthritis Res Ther. 2009;11(5):248 

In This Article

Innate-adaptive Interface

Interferon Signalling: IRF5

It is clear that type 1 interferons (IFNα and IFNβ) are of great importance in the pathogenesis of SLE. Patients with active disease have high levels of IFNα, which has multiple immunomodulatory actions,[29] including the induction of dendritic cell differentiation, the upregulation of innate immune receptors such as toll-like receptors (TLRs), the polarization of T cells towards a TH1 phenotype, and the activation of B cells. Type I interferons are produced by all cells in response to viral infection, but particularly by plasmacytoid dendritic cells in response to unmethylated CpG oligonucleotides binding to TLR-9, or RNA to TLR-7. Using a candidate gene approach targeting the IFN signalling pathway, the SNP rs2004640 in IRF5 (interferon regulatory factor 5) was found to be significantly associated with SLE (OR 1.6),[30] a risk gene confirmed in several other studies.[17,31–35] The functional consequences for IRF5 of the identified mutations are variable, but include the creation of a 5' donor splice site in an alternative exon 1, allowing the expression of several isoforms,[35] a 30 base-pair in-frame insertion/deletion variant of exon 6, a change in the 3' untranslated region, and a CGGGG insertion-deletion (indel) polymorphism, the latter two affecting mRNA stability.[32,36] Interestingly, these mutations may occur together in a haplotype, with varying degrees of associated risk. The exact role of IRF5 in IFN signalling has not been fully elucidated, but it is also critical for the gene induction programme activated by TLRs,[37] providing further biological plausibility for its importance in the pathogenesis of SLE. Haplotypes of IRF5 are also implicated in RA, and may confer either protection (OR 0.76) or predisposition (OR 1.8).[38] The same CGGGG indel allele described above also carries risk for multiple sclerosis and inflammatory bowel disease.[36]

TNF-associated Signalling Pathway: TNFAIP3 and TRAF1-C5

TNF-associated signalling pathway genes play a prominent role in the risk for both SLE and RA, and associations with variants in TNFAIP3, and the TRAF1-C5 locus have been identified.[39,40] TNFα-induced protein-3 (TNFAIP3; also known as A20) is a ubiquitin editing enzyme that acts as a negative regulator of NFκB. A20 can disassemble Lys63-linked polyubiquitin chains from targets such as TRAF6 and RIP1. A second region of A20 catalyses Lys48-linked ubiquitination that targets the molecule for degradation by the proteasome.[41] A20 modifies key mediators in the downstream signalling of TLRs that use MyD88, TNF receptors, the IL-1 receptor family, and nucleotide-oligomerization domain protein 2 (NOD2).[42]Tnfaip3 knockout mice develop severe multi-organ inflammatory disease, and the phenotype is lethal.[43] The SNP rs10499194 in TNFAIP3 carries an OR of 1.33 for RA, and rs5029939 an OR of 2.29 for SLE,[44] the latter also conferring an increased risk of haematologic or renal complications.[45]

On chromosome 9, the region containing TRAF1 (TNF receptor associated factor 1) and C5 (complement component 5) genes is associated with significant risk for RA (risk SNP OR of approximately 1.3) in most,[15,40,46–48] but not all,[5] studies. Due to linkage disequilibrium, the functional variant remains elusive. TRAF1 is principally expressed in lymphocytes, and inhibits NFκB signalling by TNF. This pathway is blocked in TRAF1 overexpression[49] whilst, conversely, Traf1-/- mice are sensitized to TNF and have exaggerated TNF-induced skin necrosis.[50]

The complement system has long been known to be involved in the pathogenesis of RA. In the collagen-induced arthritis model of RA, C5 deficiency prevents disease de novo and ameliorates existing symptoms and signs.[51,52] Interestingly, GG homozygotes at the TRAF1-C5 SNP rs3761847 with RA have a significantly increased risk of death (hazard ratio 3.96, 95% confidence interval 1.24 to 12.6, P = 0.02) from malignancy or sepsis, potentially allowing identification of patients for appropriate screening.[53]

Immunomodulatory Adhesion Molecule: ITGAM

Integrin-α-M (ITGAM), variants of which are strongly associated with SLE, forms a heterodimer with integrin-β-2 to produce αMβ2-integrin (also known as CD11b, Mac-1, or complement receptor-3), which mediates the adhesion of myeloid cells to the endothelium via ICAM-1 (Intercellular adhesion molecule-1) and recognizes the complement component iC3b. It not only has a role in cell trafficking and phagocytosis,[54] but also has other immunomodulatory functions. Antigen-presenting cells produce tolerogenic IL-10 and transforming growth factor-β on iC3b binding to CD11b,[55] and mice deficient in this receptor upregulate expression of IL-6, favouring a pro-inflammatory TH17 response.[56] Despite its implication in defective immune complex clearance in SLE, experimental evidence for a role was lacking. GWA studies, however, demonstrate a strong and significant association,[17,33,44] with an OR of 1.83 (P = 7 × 10−50) in meta-analysis.[57] The implicated SNP rs1143679 is non-synonymous, causing the substitution of histidine for arginine at amino acid 77, although this change does not affect the iC3b binding site.[58] Furthermore, although this SNP is disease associated in European and Hispanic patients, it is monomorphic in Japanese and Korean populations;[59] an explanation of its effect is therefore outstanding. It has been mentioned that CNV is important in C4 expression; the same is true for the Fcγ receptor IIIb (FCGR3B),[60] which relies on CD11b for function. Fcγ receptor IIIb is principally present on neutrophils and is important in the binding and clearance of immune complexes, therefore marking itself as a potential SLE risk gene. There is a significant association between low FCGR3B copy number and SLE. Patients with two or fewer copies of FCGR3B have an OR of 2.43 for SLE with nephritis, and 2.21 for SLE without nephritis.[61]


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