Session Title: Genetics and Genomics of Rheumatic Disease I
Session Type: Abstract Submissions (ACR)
Anterior uveitis (AU) complicates a number of autoimmune diseases including ankylosing spondylitis (AS), Behcet’s disease and sarcoidosis. It is highly heritable and HLA-B27 is the major risk factor. Functional data has suggested that AU is a T-cell mediated disease. Genes including MHC class II molecules and cytokine genes have been associated with AU. A linkage study has reported suggestive linkage at chromosome 9p21-9p24, but no non-MHC gene has been definitively associated with AU. Our aim was to use an immune focused micro-array to better characterise the genetic variants associated with AU.
Cases of AS with AU (n = 1,422), cases of AS without AU (n = 2,339), AU cases alone (n = 289) and healthy controls (HC) (n = 10,000) were recruited. The Illumina Immunochip microarray was used to genotype 190,000 autoimmune related SNPs across the genome selected for their previous identification in autoimmune phenotypes or for fine mapping of association signals already identified. Analysis was completed with the linear mixed model FaST-LMM. We report here the analysis of all AU cases compared to HC. Classical MHC alleles were imputed from genotyping data using the programme HLA*IMP.
Multiple regions previously reported to be associated with AS were significantly associated. In addition, in this analysis, one rare haplotype (minor allele frequency in controls = 0.0003) spanning the genes CCL19, CCL21 and CCL27 was associated with AU at genome wide significance (P = 2.6 x 10-9, OR = 11.4). Taqman genotyping of the lead SNP in this haplotype was completely concordant with array genotype. Five other loci implicating RGS21 (9.5 x 10-7, OR 1.2), CD28-CTLA4 (9.4 x 10-7, OR = 1.2), POP7 (1.6 x 10-6, OR = 1.3), WFDY4 (7.9 x 10-6, OR = 1.2) and CLECL16A (6.4 x 10-6, OR = 1.3) were associated at a suggestive level of significance (P < 1 x 10-5). HLA-B27 was strongly associated (P = 1 x 10-320, OR = 5.0). Conditioning on HLA-B*27, a protective association with HLA-B*07 was observed (P= 1.2 x 10-6, OR = 0.71).
Multiple SNPs implicating T cell function and co-stimulation, as well as complement and chemokine pathways were associated with AU. These findings indicate that whilst the genetic risk factors for AS and AU are similar, additional genetic risk variants influence the risk of developing AU that are not involved in AS itself
M. H. Weisman,
W. P. Maksymowych,
T. M. Martin,
J. T. Rosenbaum,
J. D. Reveille,
M. A. Brown,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-associations-in-anterior-uveitis-implicate-t-cell-co-stimulation-and-other-immune-pathways/