New insights into the genetic component of non-infectious uveitis through an Immunochip strategy.
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.



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.



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.



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.
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain.
Ana
A
Márquez
Ophthalmology Department, Hospital de León, IBIOMED, Universidad de León, León, Spain.
Miguel
M
Cordero-Coma
Immunology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
José Manuel
JM
Martín-Villa
Ophthalmology Department, Hospital Universitario Principe de Asturias, Alcalá de Henares, Spain.
Marina Begoña
MB
Gorroño-Echebarría
Rheumatology Department, Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain.
Ricardo
R
Blanco
Ophthalmology Department, Hospital Clínico San Carlos, Madrid, Spain.
David
D
Díaz Valle
Ophthalmology Department, Hospital Carlos Haya, Málaga, Spain.
María José
MJ
Del Rio
Ophthalmology Department, Hospital Donostia, San Sebastián (Guipúzcoa), Spain.
Ana
A
Blanco
Ophthalmology Department, Hospital Son Espases, Palma de Mallorca, Spain.
Jose Luis
JL
Olea
Ophthalmology Department, Hospital Universitario Rio Hortega, Valladolid, Spain.
Yolanda
Y
Cordero
Institut Universitari Barraquer, Universitat Autònoma de Barcelona, Barcelona, Spain.
María José
MJ
Capella
Ophthalmology Department, Hospital La Fe, Universidad de Valencia, Valencia, Spain.
Manuel
M
Díaz-Llopis
Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain.
Norberto
N
Ortego-Centeno
Autoimmune Diseases Research Unit, Internal Medicine Department, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
Ioana
I
Ruiz-Arruza
Ophthalmology Department, Hospital Clinic, Barcelona, Spain.
Víctor
V
Llorenç
Ophthalmology Department, Hospital Clinic, Barcelona, Spain.
Alfredo
A
Adán
Ophthalmology Department, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
Alejandro
A
Fonollosa
Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Josianne
J
Ten Berge
School of Clinical Sciences, Bristol Eye Hospital, Bristol, UK.
Denize
D
Atan
School of Clinical Sciences, Bristol Eye Hospital, Bristol, UK.
Andrew D
AD
Dick
Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, The Netherlands.|Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Joke H
JH
De Boer
Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, The Netherlands.|Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Jonas
J
Kuiper
Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Aniki
A
Rothova
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain.
Javier
J
Martín
D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014605:Uveitis / Q000235:genetics*; D044465:White People / Q000235:genetics
D006680:HLA Antigens
Immunochip; human leukocyte antigen; meta-analysis; non-anterior uveitis; non-infectious uveitis