Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma.
OBJECTIVE
A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association.


METHODS
The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts.


RESULTS
The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively).


CONCLUSIONS
This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma.
INSERM UMR1184, CEA-iMETI/Division of Immuno-Virology, Université Paris Sud, Le Kremlin-Bicêtree, France.
Gaetane
G
Nocturne
Institute of Cellular Medicine and NIHR Biomedical Research Centre for Ageing and Chronic Diseases, Newcastle, UK.
Jessica
J
Tarn
INSERM UMR1184, CEA-iMETI/Division of Immuno-Virology, Université Paris Sud, Le Kremlin-Bicêtree, France.
Saida
S
Boudaoud
Institute of Cellular Medicine and NIHR Biomedical Research Centre for Ageing and Chronic Diseases, Newcastle, UK.
James
J
Locke
INSERM UMR1184, CEA-iMETI/Division of Immuno-Virology, Université Paris Sud, Le Kremlin-Bicêtree, France Department of Rhumatologie, Hopital Bicetre, Le Kremlin Bicêtre, France.
Corinne
C
Miceli-Richard
Service de Médecine Interne, Lille, France.
Eric
E
Hachulla
Department of Rhumatologie, Hôpital, Clermont Ferrand, France.
Jean-Jacques
JJ
Dubost
Department of Rheumatology, University Hospitals Birmingham, Birmingham, UK.
Simon
S
Bowman
Department of Rheumatology, University Hospital of Strasbourg, Strasbourg, France.
Jacques-Eric
JE
Gottenberg
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Lindsey A
LA
Criswell
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Christopher J
CJ
Lessard
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Kathy L
KL
Sivils
U1109, INSERM and University of Strasbourg, Strasbourg, France Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France and Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Raphael
R
Carapito
Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France and Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Siamak
S
Bahram
INSERM UMR1184, CEA-iMETI/Division of Immuno-Virology, Université Paris Sud, Le Kremlin-Bicêtree, France.
Raphaèle
R
Seror
Institute of Cellular Medicine and NIHR Biomedical Research Centre for Ageing and Chronic Diseases, Newcastle, UK.
Wan-Fai
WF
Ng
Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France.
Xavier
X
Mariette
D016022:Case-Control Studies; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005602:France; D018095:Germ-Line Mutation / Q000235:genetics*; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016015:Logistic Models; D008223:Lymphoma / Q000150:complications / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics; D015999:Multivariate Analysis; D009182:Mycosis Fungoides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012859:Sjogren's Syndrome / Q000150:complications / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D006113:United Kingdom; D044465:White People / Q000235:genetics
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
Autoimmunity; B cells; Sjøgren's Syndrome