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

Ana Márquez; Miguel Cordero-Coma; José Manuel Martín-Villa; Marina Begoña Gorroño-Echebarría; Ricardo Blanco; David Díaz Valle; María José Del Rio; Ana Blanco; Jose Luis Olea; Yolanda Cordero; María José Capella; Manuel Díaz-Llopis; Norberto Ortego-Centeno; Ioana Ruiz-Arruza; Víctor Llorenç; Alfredo Adán; Alejandro Fonollosa; Josianne Ten Berge; Denize Atan; Andrew D Dick; Joke H De Boer; Jonas Kuiper; Aniki Rothova; Javier Martín

doi:10.1136/jmedgenet-2016-104144

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

Ana Márquez, Miguel Cordero-Coma, José Manuel Martín-Villa, Marina Begoña Gorroño-Echebarría, Ricardo Blanco, David Díaz Valle, María José Del Rio, Ana Blanco, Jose Luis Olea, Yolanda Cordero, María José Capella, Manuel Díaz-Llopis, Norberto Ortego-Centeno, Ioana Ruiz-Arruza, Víctor Llorenç, Alfredo Adán, Alejandro Fonollosa, Josianne Ten Berge, Denize Atan, Andrew D DickJoke H De Boer, Jonas Kuiper, Aniki Rothova, Javier Martín

Research output: Contribution to journal › Article (Academic Journal) › peer-review

12 Citations (Scopus)

569 Downloads (Pure)

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.

Original language	English
Pages (from-to)	38-46
Number of pages	9
Journal	Journal of Medical Genetics
Volume	54
Issue number	1
Early online date	8 Sept 2016
DOIs	https://doi.org/10.1136/jmedgenet-2016-104144
Publication status	Published - Jan 2017

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This is the author accepted manuscript (AAM). The final published version (version of record) is available online via BMJ at http://jmg.bmj.com/content/54/1/38. Please refer to any applicable terms of use of the publisher.
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12 Citations
1 Article (Academic Journal)

Tumor necrosis factor polymorphisms associated with tumor necrosis factor production influence the risk of idiopathic intermediate uveitis
Atan, D., Heissigerova, J., Kuffová, L., Hogan, A., Kilmartin, D. J., Forrester, J. V., Bidwell, J. L., Dick, A. D. & Churchill, A. J., 28 Jan 2013, In: Molecular Vision. 19, p. 184-195 12 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-review

1 Invited talk

Oxford Eye Hospital Regional Opththalmology meeting
Denize Atan (Participant)
14 May 2007
Activity: Participating in or organising an event types › Invited talk

Dr Denize Atan
- Denize.Atanbristol.acuk
- Bristol Medical School (THS) - Associate Professor in Neuro-ophthalmology, Neuroscience and Genetics
- Infection and Immunity
- Ophthalmology
- Bristol Vision Institute
- Bristol Neuroscience
Person: Academic , Member

Cite this

Márquez, A., Cordero-Coma, M., Martín-Villa, J. M., Gorroño-Echebarría, M. B., Blanco, R., Díaz Valle, D., Del Rio, M. J., Blanco, A., Olea, J. L., Cordero, Y., Capella, M. J., Díaz-Llopis, M., Ortego-Centeno, N., Ruiz-Arruza, I., Llorenç, V., Adán, A., Fonollosa, A., Ten Berge, J., Atan, D., ... Martín, J. (2017). New insights into the genetic component of non-infectious uveitis through an Immunochip strategy. Journal of Medical Genetics, 54(1), 38-46. https://doi.org/10.1136/jmedgenet-2016-104144

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title = "New insights into the genetic component of non-infectious uveitis through an Immunochip strategy",

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.",

author = "Ana M{\'a}rquez and Miguel Cordero-Coma and Mart{\'i}n-Villa, {Jos{\'e} Manuel} and Gorro{\~n}o-Echebarr{\'i}a, {Marina Bego{\~n}a} and Ricardo Blanco and {D{\'i}az Valle}, David and {Del Rio}, {Mar{\'i}a Jos{\'e}} and Ana Blanco and Olea, {Jose Luis} and Yolanda Cordero and Capella, {Mar{\'i}a Jos{\'e}} and Manuel D{\'i}az-Llopis and Norberto Ortego-Centeno and Ioana Ruiz-Arruza and V{\'i}ctor Lloren{\c c} and Alfredo Ad{\'a}n and Alejandro Fonollosa and {Ten Berge}, Josianne and Denize Atan and Dick, {Andrew D} and {De Boer}, {Joke H} and Jonas Kuiper and Aniki Rothova and Javier Mart{\'i}n",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2017",

month = jan,

doi = "10.1136/jmedgenet-2016-104144",

language = "English",

volume = "54",

pages = "38--46",

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Márquez, A, Cordero-Coma, M, Martín-Villa, JM, Gorroño-Echebarría, MB, Blanco, R, Díaz Valle, D, Del Rio, MJ, Blanco, A, Olea, JL, Cordero, Y, Capella, MJ, Díaz-Llopis, M, Ortego-Centeno, N, Ruiz-Arruza, I, Llorenç, V, Adán, A, Fonollosa, A, Ten Berge, J, Atan, D , Dick, AD, De Boer, JH, Kuiper, J, Rothova, A & Martín, J 2017, 'New insights into the genetic component of non-infectious uveitis through an Immunochip strategy', Journal of Medical Genetics, vol. 54, no. 1, pp. 38-46. https://doi.org/10.1136/jmedgenet-2016-104144

TY - JOUR

T1 - New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

AU - Márquez, Ana

AU - Cordero-Coma, Miguel

AU - Martín-Villa, José Manuel

AU - Gorroño-Echebarría, Marina Begoña

AU - Blanco, Ricardo

AU - Díaz Valle, David

AU - Del Rio, María José

AU - Blanco, Ana

AU - Olea, Jose Luis

AU - Cordero, Yolanda

AU - Capella, María José

AU - Díaz-Llopis, Manuel

AU - Ortego-Centeno, Norberto

AU - Ruiz-Arruza, Ioana

AU - Llorenç, Víctor

AU - Adán, Alfredo

AU - Fonollosa, Alejandro

AU - Ten Berge, Josianne

AU - Atan, Denize

AU - Dick, Andrew D

AU - De Boer, Joke H

AU - Kuiper, Jonas

AU - Rothova, Aniki

AU - Martín, Javier

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2017/1

Y1 - 2017/1

N2 - 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.

AB - 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.

U2 - 10.1136/jmedgenet-2016-104144

DO - 10.1136/jmedgenet-2016-104144

M3 - Article (Academic Journal)

C2 - 27609017

SN - 0022-2593

VL - 54

SP - 38

EP - 46

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 1

ER -

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

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Research output

Tumor necrosis factor polymorphisms associated with tumor necrosis factor production influence the risk of idiopathic intermediate uveitis

Activities

Oxford Eye Hospital Regional Opththalmology meeting

Profiles

Dr Denize Atan

Cite this