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

Philip C. Robinson, Theodora A M Claushuis, Adrian Cortes, Tammy Martin, David M. Evans, Paul Leo, Pamela Mukhopadhyay, Linda A. Bradbury, Katie Cremin, Jessica Harris, Walter P. Maksymowych, Robert D. Inman, Proton Rahman, Nigil Haroon, Lianne Gensler, Joseph E. Powell, Irene E. Van Der Horst-Bruinsma, Alex W. Hewitt, Jamie E. Craig, Lyndell L. LimDenis Wakefield, Peter McCluskey, Valentina Voigt, Peter Fleming, Mariapia Degli-Esposti, Jennifer J. Pointon, Michael H. Weisman, B. Paul Wordsworth, John D. Reveille, James (Jim) Rosenbaum, Matthew A. Brown

Research output: Contribution to journalArticle

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Abstract

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.

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.

Original languageEnglish (US)
Pages (from-to)140-151
Number of pages12
JournalArthritis and Rheumatology
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2015

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Anterior Uveitis
Ankylosing Spondylitis
Dissection
Interleukin-10
HLA-B27 Antigen
Intergenic DNA
Genetic Loci
HLA-B Antigens
Genome-Wide Association Study
Genetic Predisposition to Disease
Major Histocompatibility Complex
Inflammatory Bowel Diseases
Genes
Reverse Transcription
Single Nucleotide Polymorphism
Healthy Volunteers
Chromosomes
Genome

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

Cite this

Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. / Robinson, Philip C.; Claushuis, Theodora A M; Cortes, Adrian; Martin, Tammy; Evans, David M.; Leo, Paul; Mukhopadhyay, Pamela; Bradbury, Linda A.; Cremin, Katie; Harris, Jessica; Maksymowych, Walter P.; Inman, Robert D.; Rahman, Proton; Haroon, Nigil; Gensler, Lianne; Powell, Joseph E.; Van Der Horst-Bruinsma, Irene E.; Hewitt, Alex W.; Craig, Jamie E.; Lim, Lyndell L.; Wakefield, Denis; McCluskey, Peter; Voigt, Valentina; Fleming, Peter; Degli-Esposti, Mariapia; Pointon, Jennifer J.; Weisman, Michael H.; Wordsworth, B. Paul; Reveille, John D.; Rosenbaum, James (Jim); Brown, Matthew A.

In: Arthritis and Rheumatology, Vol. 67, No. 1, 01.01.2015, p. 140-151.

Research output: Contribution to journalArticle

Robinson, PC, Claushuis, TAM, Cortes, A, Martin, T, Evans, DM, Leo, P, Mukhopadhyay, P, Bradbury, LA, Cremin, K, Harris, J, Maksymowych, WP, Inman, RD, Rahman, P, Haroon, N, Gensler, L, Powell, JE, Van Der Horst-Bruinsma, IE, Hewitt, AW, Craig, JE, Lim, LL, Wakefield, D, McCluskey, P, Voigt, V, Fleming, P, Degli-Esposti, M, Pointon, JJ, Weisman, MH, Wordsworth, BP, Reveille, JD, Rosenbaum, JJ & Brown, MA 2015, 'Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis', Arthritis and Rheumatology, vol. 67, no. 1, pp. 140-151. https://doi.org/10.1002/art.38873
Robinson, Philip C. ; Claushuis, Theodora A M ; Cortes, Adrian ; Martin, Tammy ; Evans, David M. ; Leo, Paul ; Mukhopadhyay, Pamela ; Bradbury, Linda A. ; Cremin, Katie ; Harris, Jessica ; Maksymowych, Walter P. ; Inman, Robert D. ; Rahman, Proton ; Haroon, Nigil ; Gensler, Lianne ; Powell, Joseph E. ; Van Der Horst-Bruinsma, Irene E. ; Hewitt, Alex W. ; Craig, Jamie E. ; Lim, Lyndell L. ; Wakefield, Denis ; McCluskey, Peter ; Voigt, Valentina ; Fleming, Peter ; Degli-Esposti, Mariapia ; Pointon, Jennifer J. ; Weisman, Michael H. ; Wordsworth, B. Paul ; Reveille, John D. ; Rosenbaum, James (Jim) ; Brown, Matthew A. / Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 1. pp. 140-151.
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abstract = "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.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.",
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T1 - Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis

AU - Robinson, Philip C.

AU - Claushuis, Theodora A M

AU - Cortes, Adrian

AU - Martin, Tammy

AU - Evans, David M.

AU - Leo, Paul

AU - Mukhopadhyay, Pamela

AU - Bradbury, Linda A.

AU - Cremin, Katie

AU - Harris, Jessica

AU - Maksymowych, Walter P.

AU - Inman, Robert D.

AU - Rahman, Proton

AU - Haroon, Nigil

AU - Gensler, Lianne

AU - Powell, Joseph E.

AU - Van Der Horst-Bruinsma, Irene E.

AU - Hewitt, Alex W.

AU - Craig, Jamie E.

AU - Lim, Lyndell L.

AU - Wakefield, Denis

AU - McCluskey, Peter

AU - Voigt, Valentina

AU - Fleming, Peter

AU - Degli-Esposti, Mariapia

AU - Pointon, Jennifer J.

AU - Weisman, Michael H.

AU - Wordsworth, B. Paul

AU - Reveille, John D.

AU - Rosenbaum, James (Jim)

AU - Brown, Matthew A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.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.

AB - 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.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.

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