Association of genes in the NF-κB pathway with antibody-positive primary Sjögren's syndrome.
Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 × 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 × 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.
Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Gunnel
G
Nordmark
Chuan
C
Wang
Lilian
L
Vasaitis
Per
P
Eriksson
Elke
E
Theander
Marika
M
Kvarnström
Helena
H
Forsblad-d'Elia
Helmi
H
Jazebi
Christopher
C
Sjöwall
Tove Ragna
TR
Reksten
Johan G
JG
Brun
Malin V
MV
Jonsson
Svein J
SJ
Johnsen
Marie
M
Wahren-Herlenius
Roald
R
Omdal
Roland
R
Jonsson
Simon
S
Bowman
Wan-Fai
WF
Ng
Maija-Leena
ML
Eloranta
Ann-Christine
AC
Syvänen
D000974:Antibodies, Antinuclear / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000097585:SS-B Antigen; D000099207:SS-A Antigen
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000097585:SS-B Antigen; D000099207:SS-A Antigen; C489548:NFKB1 protein, human; C035356:SS-A antibodies; C035357:SS-B antibodies; C117046:TNIP1 protein, human; C496565:IKBKE protein, human; C076529:TNFAIP3 protein, human