Genetics of Rheumatic Disease

Alex Clarke; Timothy J Vyse


Arthritis Res Ther. 2009;11(5):248 

In This Article

Lymphocyte Differentiation

T Cell Receptor Signalling: PTPN22

Outside the HLA region, the first reproducible genetic association for RA came with the implication of PTPN22 from a candidate gene approach[62] based on linkage analysis identification of a susceptibility locus at 1p13.[63] It has remained the strongest and most consistent association mapped by GWA studies in RA. A role in SLE has also been identified.[17] The OR for the risk allele is around 1.75 in RA, and 1.5 in SLE. However, it should be noted that this allele (encoding the R620W mutation) is monomorphic or not disease associated in Korean or Japanese patients.[64,65]PTPN22 encodes lymphoid tyrosine phosphatase (LYP), a protein tyrosine phosphatase that inhibits T cell receptor signalling, decreasing IL-2 production. The disease associated SNP is responsible for a change from arginine to tryptophan at position 620, which inhibits binding to the SH3 domain of carboxy-terminal Src kinase. This in turn appears to enhance dephosphorylation of tyrosine residues in the Src family kinases Lck, FynT, and ZAP-70.[66,67] The overall effect of the mutation is a reduction in T cell receptor signalling. The pathogenic effect of this is unclear, but may relate to impaired negative selection in the thymus, or lead to a reduction in regulatory T cells.[68] Conversely, the R623Q variant of PTPN22, which is a loss-of-function mutation affecting the phosphatase activity of LYP, is protective against SLE.[69]PTPN22 does not appear to be a risk gene for AS.[70]

Polarization Towards TH1 and TH17 Phenotypes: STAT4 and IL23R

STAT4 encodes signal transducer and activation of transcription factor-4, responsible for signalling by IL-12, IL-23, and type 1 IFNs.[71] STAT4 polarizes T cells towards TH1 and TH17 phenotypes, which has the potential to promote autoimmunity.[72] In RA the OR for the risk allele of SNP rs7574865 is 1.32 in one case-control study,[73] with a less strong disease association at rs11893432 in a meta-analysis of GWA studies (OR 1.14).[15] There is convincing evidence that STAT4 is a risk locus for SLE in multiple racial groups,[33,74] and it may be theorized that interference in type I IFN signalling may be the underlying pathogenic mechanism in this case. Distinctive disease pathways could, therefore, emerge from mutations in a single gene. The WTCCC AS study identified IL23R as a risk gene in AS.[24] IL-23 is instrumental in the development of T cells with the pro-inflammatory TH17 phenotype,[75] and IL23R has been linked to psoriasis, ulcerative colitis, and Crohn's disease in GWA studies.[5,76,77] An interesting connection between these conditions, all of which may share common clinical features, is thus made. In AS the risk SNP rs11209032 confers an OR of 1.3.

B Cell Activation

B cells are a population long suspected to be important in autoimmune rheumatic disease, and the benefits of their depletion in RA and SLE has resurrected interest in their pathogenic role. The risk genes identified so far are involved in signalling from the B cell receptor (BCR). BLK encodes a Src family tyrosine kinase restricted to the B cell lineage and is poorly understood. Risk alleles in the region upstream of the transcription initiation site are associated with SLE (OR 1.39, P = 1 × 10−10) and reduce levels of BLK mRNA.[33] BANK1 (B cell scaffold protein with ankyrin repeats-1) undergoes tyrosine phosphorylation upon B cell activation by the BCR, leading to an increase in intracellular calcium through the inositol trisphosphate mechanism.[78] The non-synonymous SNP rs10516487 in BANK1, which substitutes histidine for arginine at amino acid 61, also has disease association (OR 1.38).[79] The functional consequence of this may be higher affinity for the inositol trisphosphate receptor, as the substitution is located in the binding site.

Lyn, another Src tyrosine kinase, is important in determining signalling thresholds for myeloid and B cells. On BCR ligation, it phosphorylates tyrosine residues of Syk, an activating tyrosine kinase, CD19, and the immunoreceptor tyrosine-based activation motifs (ITAMs) of the Igα/Igβ subunits of the BCR. However, it also has a critical regulatory role, mediated by phosphorylation of the inhibitory motifs of CD22 and Fcγ RIIB, which in turn activate SH2-domain containing phosphatases, leading to dephosphorylation and deactivation of a number of signalling intermediaries.[80] Lyn-/- mice develop severe autoimmunity associated with glomerulonephritis.[81] An association between SNPs in LYN and SLE, identified initially in the SLEGEN GWA study,[17] has been recently confirmed in a case-control study.[82] The most associated SNP, rs6983130, is near the primary transcription initiation site.

OX40L, a member of the TNF super-family encoded by TNFSF4 (TNF superfamily 4), is associated with SLE. The cross-talk between B lymphocytes and dendritic cells expressing OX40L, and T cells that express its receptor, OX40, serves to enhance the adaptive immune response.[83] An upstream TNFSF4 haplotype, associated with SLE, enhances gene expression in vitro,[84,85] although the mechanism responsible for the deleterious effects observed remains to be established.

Despite the importance of B cells in the pathogenesis of RA, none of the gene effects described above have been identified in the current generation of GWA studies. However, variants at CD40 in European patients do carry risk.[15] CD40 expressed on B cells, via interaction with its ligand CD154 on CD4+ T cells, promotes immunoglobulin class switching, and germinal centre formation. B cells, however, also have a regulatory role, likely to be mediated by IL-10, and disruption of this function may be another route to autoimmune disease.[86]

Post-translational Modification: PADI4

Peptidyl arginine deiminase-4 (PADI4) is a member of the enzyme family responsible for the post-translational citrullination of arginine residues in RA synovium, subsequently recognized by anti-cyclic citrullinated protein antibodies. In Japanese[87] and Korean patients,[88] case-control association studies have identified functional haplotypes of PADI4 conferring risk of RA. However, in Caucasian populations this association is inconsistent.[89–91]


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