The emerging overlap of autoimmune disease susceptibility loci makes many of the newly discovered T1D and CD loci appealing candidates for investigation as possible JIA susceptibility loci. There is already some evidence for the overlap of JIA and T1D susceptibility loci, with confirmed association of genes such as the major histocompatibility complex, PTPN22
region and CCR5
with both diseases.5 10–12
By investigating confirmed CD and T1D loci in JIA we have identified a novel locus conferring susceptibility to JIA. This SNP lies within the Lim domain containing preferred translocation partner in lipoma (LPP
) gene. SNPs in LPP
show validated association with CD.13 14
Interestingly, the rs1464510 SNP does not appear to be associated with T1D2
and studies in RA show conflicting results: in one large UK population study, no association was detected (ptrend
=0.82, OR=1.01, 95% CI 0.94 to 1.08) (Eyre et al
, submitted) while in a Dutch population, modest evidence for association was reported (p=0.012, OR=1.14, 95% CI 1.03 to 1.26).3
has a number of known functions; it is important in cell migration, cell adhesion and acts as a versatile scaffolding and adaptor protein.15
was identified as a substrate of the protein-tyrosine phosphatase 1B, a negative regulator of multiple signalling pathways downstream of receptor tyrosine kinases and functionally linked to Ras signalling.16
Further work will be required to determine which of the multiple potential pathways with which the protein interacts is affected by the variants that predispose to autoimmune disease.
We also found weak evidence for association of a SNP, rs653178, in the SH2B3/ATXN2
gene region with JIA, though it did not remain significant after correction for multiple testing. The SNP lies within intron 1 of the ATXN2
gene which lies adjacent to the SH2B3
gene. This SNP is in complete linkage disequilibrium (r2
=1) with the SNP, rs3184504, in SH2B3
, and both SNPs show validated association with CD.13 14
rs3184504 has been also been associated with both RA and CD in a Dutch population.3
rs3184504 variant is a non-synonymous SNP, R262W, located in exon 3 of the gene. SH2B3
encodes the T-cell adapter protein Lnk, which regulates T-cell receptor-, growth factor- and cytokine receptor-mediated signalling. It has been shown to be a negative regulator of tumour necrosis factor α signalling in human endothelial cells.17
Another SNP, rs17696736, within the adjacent gene c12orf30
, has also been reported to be associated with JIA in a US case–control cohort.18
There is only modest linkage disequilibrium between that SNP and the SNP tested in our study (r2
=0.5). Hence, both may simply be markers of an, as yet, un-genotyped causal variant or there may be independent effects in the region.
We also found that the SNP, rs17810546, which lies 5′ to the IL12A gene, showed differences in allele frequencies across the ILAR subtypes and this was driven by a strong association with ERA. This is a subgroup comprising mainly male, HLA-B27-positive patients and it is characterised by the presence of enthesitis and arthritis. It may progressively involve the sacroiliac joints and spine, with symptoms similar to ankylosing spondylitis. It is important to note that the numbers in this subgroup are small (n=61) so this finding should be interpreted with caution and will require validation in an independent cohort. To date the IL12A gene has not been associated with ankylosing spondylitis.
Although none of the other SNPs studied showed significant association with JIA, we cannot unequivocally rule out association for many of these loci. This is owing to the limited power in this study to detect some of the loci that were identified in the studies for CD and T1D, which had much larger sample sizes. We had >80% power to detect an effect at RGS1, IL18RAP, IL12A, INS and ERBB3 and therefore feel more confident that the SNPs tested at those loci are not associated with JIA. OR plots for CD and T1D susceptibility genes across the different autoimmune diseases, JIA, RA, T1D and CD, are shown in and , respectively.
Figure 1 Odds ratio (OR) plots for juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CD) for confirmed CD loci. Data for T1D and CD from Smyth et al,2 for RA from Barton et al19 20 and Eyre et al, submitted, (more ...)
Figure 2 Odds ratio (OR) plots for juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CD) for confirmed T1D loci. Data for T1D and CD from Smyth et al,2 for RA from Barton et al19 20 and Eyre et al, submitted, (more ...)
In conclusion we have identified novel association of the LPP gene and show weak but confirmatory association of the ATXN2/SH2B3/c12orf30 region with JIA in a UK cohort. In addition, we report an ERA subtype-specific association with the IL12A gene. Investigation of all these loci in independent JIA case–control cohorts followed by meta-analysis will be required to confidently confirm or refute these as JIA susceptibility loci. Nonetheless, the approach of targeting variants associated with other autoimmune diseases is already yielding insights into the genetic complexity underlying susceptibility to this serious childhood disease.