Genetic Associations In Anterior Uveitis Implicate T-Cell Co-Stimulation and Other Immune Pathways

Robinson, Philip, Claushuis, Dorith, Leo, Paul, Mukhopadhyay, Pamela, Wordsworth, P., Weisman, Michael H., Maksymowych, Walter P., Rahman, Proton, Inman, Robert, Hewitt, Alex, Martin, Tammy M., Rosenbaum, James T., Wakefield, Dennis, Reveille, John D. and Brown, Matthew A. (2013). Genetic Associations In Anterior Uveitis Implicate T-Cell Co-Stimulation and Other Immune Pathways. In: Abstract Supplement 2013 Annual Meeting. 77th Annual Meeting of the American College of Rheumatology / 48th Annual Meeting of the Association of Rheumatology Health Professionals, San Diego CA, United States, (S722-S723). 25-30 October 2013 Proceedings title Abstract Supplement 2013 Annual Meeting. doi:10.1002/art.38216


Author Robinson, Philip
Claushuis, Dorith
Leo, Paul
Mukhopadhyay, Pamela
Wordsworth, P.
Weisman, Michael H.
Maksymowych, Walter P.
Rahman, Proton
Inman, Robert
Hewitt, Alex
Martin, Tammy M.
Rosenbaum, James T.
Wakefield, Dennis
Reveille, John D.
Brown, Matthew A.
Title of paper Genetic Associations In Anterior Uveitis Implicate T-Cell Co-Stimulation and Other Immune Pathways
Conference name 77th Annual Meeting of the American College of Rheumatology / 48th Annual Meeting of the Association of Rheumatology Health Professionals
Conference location San Diego CA, United States
Conference dates 25-30 October 2013 Proceedings title Abstract Supplement 2013 Annual Meeting
Proceedings title Abstract Supplement 2013 Annual Meeting   Check publisher's open access policy
Journal name Arthritis and Rheumatism   Check publisher's open access policy
Place of Publication Hoboken, NJ United States
Publisher John Wiley and Sons
Publication Year 2013
Year available 2013
Sub-type Published abstract
DOI 10.1002/art.38216
Open Access Status
ISSN 0004-3591
1529-0131
2326-5205
Volume 65
Issue S10
Start page S722
End page S723
Total pages 2
Language eng
Formatted Abstract/Summary
Background/Purpose:
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.

Methods:
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.

Results:
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).

Conclusion:
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
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes DOI is for abstracts published on pages S1-S1331

Document type: Conference Paper
Collection: UQ Diamantina Institute Publications
 
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