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Original article
New insights into the genetic component of non-infectious uveitis through an Immunochip strategy
  1. Ana Márquez1,
  2. Miguel Cordero-Coma2,
  3. José Manuel Martín-Villa3,
  4. Marina Begoña Gorroño-Echebarría4,
  5. Ricardo Blanco5,
  6. David Díaz Valle6,
  7. María José del Rio7,
  8. Ana Blanco8,
  9. Jose Luis Olea9,
  10. Yolanda Cordero10,
  11. María José Capella11,
  12. Manuel Díaz-Llopis12,
  13. Norberto Ortego-Centeno13,
  14. Ioana Ruiz-Arruza14,
  15. Víctor Llorenç15,
  16. Alfredo Adán15,
  17. Alejandro Fonollosa16,
  18. Josianne ten Berge17,
  19. Denize Atan18,
  20. Andrew D Dick18,
  21. Joke H De Boer19,20,
  22. Jonas Kuiper19,20,
  23. Aniki Rothova17,
  24. Javier Martín1
  1. 1Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC, PTS Granada, Granada, Spain
  2. 2Ophthalmology Department, Hospital de León, IBIOMED, Universidad de León, León, Spain
  3. 3Immunology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
  4. 4Ophthalmology Department, Hospital Universitario Principe de Asturias, Alcalá de Henares, Spain
  5. 5Rheumatology Department, Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain
  6. 6Ophthalmology Department, Hospital Clínico San Carlos, Madrid, Spain
  7. 7Ophthalmology Department, Hospital Carlos Haya, Málaga, Spain
  8. 8Ophthalmology Department, Hospital Donostia, San Sebastián (Guipúzcoa), Spain
  9. 9Ophthalmology Department, Hospital Son Espases, Palma de Mallorca, Spain
  10. 10Ophthalmology Department, Hospital Universitario Rio Hortega, Valladolid, Spain
  11. 11Institut Universitari Barraquer, Universitat Autònoma de Barcelona, Barcelona, Spain
  12. 12Ophthalmology Department, Hospital La Fe, Universidad de Valencia, Valencia, Spain
  13. 13Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain
  14. 14Autoimmune Diseases Research Unit, Internal Medicine Department, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
  15. 15Ophthalmology Department, Hospital Clinic, Barcelona, Spain
  16. 16Ophthalmology Department, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
  17. 17Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands
  18. 18School of Clinical Sciences, Bristol Eye Hospital, Bristol, UK
  19. 19Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, The Netherlands
  20. 20Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr Ana Márquez, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n, Armilla, Granada 18016, Spain; anamaort{at}ipb.csic.es

Abstract

Background Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci.

Methods 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method.

Results The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci.

Conclusions We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition.

  • non-infectious uveitis
  • non-anterior uveitis
  • meta-analysis
  • human leukocyte antigen
  • Immunochip

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Footnotes

  • Correction notice This paper has been updated since it first published online. The author name Miguel Cordero-Coma has been corrected.

  • Contributors AM, JM and MC-C were involved in the conception and design of the study and contributed in the analysis and interpretation of data. AM drafted the manuscript. MC-C, JMM-V, MBG-E, RB, DDV, MJdR, AB, JLO, YC, MJC, MD-L, NO-C, IR-A, VL, AA, AF, JtB, DA, ADD, JHDB, JK and AR collected samples and participated in analysis and interpretation of data. MC-C, JMM-V, MBG-E, RB, DDV, MJdR, AB, JLO, YC, MJC, MD-L, NO-C, IR-A, VL, AA, AF, JtB, DA, ADD, JHDB, JK, AR and JM revised critically the manuscript draft. All authors approved the final version of the manuscript.

  • Funding This study was supported by AbbVie Pharmaceutical. AM is recipient of a Juán de la Cierva fellowship (IJCI-2014-20322) from the Spanish Ministry of Economy and Competitiveness.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study was approved by Comité de Bioética del Consejo Superior de Investigaciones Científicas and the Local Ethical Committees of the different participating centres.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All meta-analysis results of this project are available.

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