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Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis.

ABSTRACT: OBJECTIVE:To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). METHODS:We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS:A comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10(-8)). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10(-6)). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. CONCLUSION:These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

SUBMITTER: Robinson PC

PROVIDER: S-EPMC4302162 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis.

Robinson Philip C PC Claushuis Theodora A M TA Cortes Adrian A Martin Tammy M TM Evans David M DM Leo Paul P Mukhopadhyay Pamela P Bradbury Linda A LA Cremin Katie K Harris Jessica J Maksymowych Walter P WP Inman Robert D RD Rahman Proton P Haroon Nigil N Gensler Lianne L Powell Joseph E JE van der Horst-Bruinsma Irene E IE Hewitt Alex W AW Craig Jamie E JE Lim Lyndell L LL Wakefield Denis D McCluskey Peter P Voigt Valentina V Fleming Peter P Degli-Esposti Mariapia M Pointon Jennifer J JJ Weisman Michael H MH Wordsworth B Paul BP Reveille John D JD Rosenbaum James T JT Brown Matthew A MA

Arthritis & rheumatology (Hoboken, N.J.) 20150101 1

<h4>Objective</h4>To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS).<h4>Methods</h4>We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk ...[more]

PMID: 25200001

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Project description:BACKGROUND:Anterior uveitis is the most common extra-articular manifestation of ankylosing spondylitis (AS). AS-related anterior uveitis frequently presents as acute, recurrent iridocyclitis; therefore, AS is often initially suspected by an ophthalmologist, not by a rheumatologist. In this study, we aimed to investigate the relationship between the recurrence of anterior uveitis and the subsequent incidence of AS. METHODS:From a national sample cohort, 10,483 patients with new-onset uveitis between 2004 and 2013 and 52415 matched control subjects who had never experienced uveitis were selected. Among the patients with new-onset uveitis, a subpopulation of patients with recurrent uveitis, defined as a minimum 120-day reported interval between consecutive claims of uveitis (based on diagnostic codes) treated with local or systemic steroids or immune-modulating drugs, was identified. The incidence rates of AS were calculated according to the number of episodes of uveitis, and the incidence rate ratios (IRRs) were derived on the basis of the incidence rate in the control group. RESULTS:The incidence rate per 100,000 person-years of AS after the first uveitis episode was 121.5, whereas the incidence in the control group was 16.9 (IRR, 7.40; 95% CI, 4.99-10.98); after the second uveitis episode, the IRR increased to 17.71 (95% CI, 10.44-30.06). In male and female patients with recurrent uveitis, the incidence rates of AS were 284.1 and 268.7 per 100,000 person-years, respectively. In patients aged under 40 years, the IRR of the recurrent uveitis group was 46.78 (95% CI, 19.61-111.61). In patients aged over 59 years, AS incidence in the recurrent uveitis group did not differ from that in the control group. CONCLUSIONS:The risk of subsequent AS increased with the number of episodes of anterior uveitis. This quantitative evidence could contribute to the establishment of a rationale for ancillary workup for possible systemic associations in patients with recurrent uveitis.

Project description:<p><strong>BACKGROUND: </strong>It has been reported that the gut microbiome is involved in the pathogenesis of uveitis, but the specific pathogenic microbes and metabolites in different types of uveitis are still unclear.</p><p><strong style='color: rgb(54, 54, 54);'>METHODS</strong><strong>: </strong>Microbiome and metabolites were detected using 16S ribosomal DNA and LC‒MS/MS (liquid chromatography tandem mass spectrometry) in 45 individuals, including 16 patients with Vogt Koyanagi Harada (VKH), 11 patients with acute anterior uveitis (AAU) and 18 healthy controls.</p><p><strong style='color: rgb(54, 54, 54);'>RESULT:</strong> The diversity of intestinal microbes among the VKH, AAU and control groups was not significantly different. 13 specific microbes and 38 metabolites were detected in the VKH group, and 7 metabolites (vanillin, erythro-isoleucine, pyrimidine, 1-aminocyclopropanecarboxylic acid, beta-tocopherol, (-)-gallocatechin and N1-methyl-4-pyridone-3-carboxamide) significantly changed only in patients with VKH, which mainly acted on nicotinamide and nicotinamide metabolism and biotin metabolism (p<0.05). Compared with the VKH group, the AAU group had milder intestinal changes. Only 11 specific microbes and 29 metabolites changed in the AAU group, while these metabolites were not specific (p<0.05). These metabolites mainly acted on arachidonic acid metabolism. In addition, 3 microbes and 2 metabolites had the same changes in the VKH and AAU groups (p<0.05). Multiple correlations were found between gut microbes and metabolites in the VKH and AAU groups. 6 microbes (Pediococcus, Pseudomonas, Rhodococcus, Photobacterium, Gardnerella and Lawsonia) and 2 metabolites (pyrimidine and gallocatechin) as biomarkers could effectively distinguish patients with VKH from patients with AAU and healthy individuals, with AUC (area under the curve) values greater than 82%. 4 microbes (Lentilactobacillus, Lachnospiraceae_UCG-010, Cetobacterium, Liquorilactobacillus) could distinguish patients with AAU from patients with VKH and healthy controls with AUC>76%.</p><p><strong style='color: rgb(54, 54, 54);'>CONCLUSION: </strong>Significant differences in intestinal microbes and metabolites suggest their different roles in the pathogenesis of uveitis entities. Changes in the metabolism of certain B vitamins may be involved in the pathogenesis of VKH.</p>

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Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis.

Publications

Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis.

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