| 1. |
- Li, He, et al.
(författare)
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Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
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| 2. |
- Nordmark, Gunnel, et al.
(författare)
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Association of Genes in the NF-κB Pathway with Antibody-Positive Primary Sjögren's Syndrome
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 78:5, s. 447-454
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjogrens 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-B in primary SS. NF-B 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-B and of IKBKE (IKK epsilon), which is an NF-B 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=3.4x10(-5), OR=1.33, 95%CI: 1.16-1.52 for rs3792783 and P=1.3x10(-3), OR=1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P=5.7x10(-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.
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| 3. |
- Reksten, Tove Ragna, et al.
(författare)
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Genetic associations to germinal centre formation in primary Sjögren's syndrome
- 2014
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 73:6, s. 1253-1258
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrimary Sjögren's syndrome (pSS) is an autoimmune rheumatic disease mainly characterised by focal mononuclear cell infiltration in the salivary and lacrimal glands, and by the symptoms xerostomia and keratoconjunctivitis sicca. Germinal centre-like structures (GC) are found in the minor salivary glands of approximately 25% of patients. In this study, we aimed to assess genetic variations in pSS patients with GC-like formations (GC+) compared with patients without such formations (GC−).MethodsMinor salivary gland biopsies from Swedish and Norwegian pSS patients (n=320) were evaluated for GC-like formations, identifying 76 GC+ and 244 GC− patients. A panel of 1536 single-nucleotide polymorphisms (SNPs) in 107 genes was genotyped. Minor allele frequencies in GC+ and GC− patients were compared using Fisher's exact test, and associations were considered significant when p<4.7×10−4 and suggestive when p<0.01.ResultsIn this case-only analysis, we identified two SNPs in CCL11 (eotaxin) associated with GC-like structures (p<4.7×10−4, OR 0.45 and 0.41, respectively). A haplotype of the two minor alleles was associated with GC status with p=2.6×10−4, OR 0.40. Suggestive associations (p<0.01) were found in SNPs in the B cell activation and/or GC-formation related genes AICDA, BANK1 and BCL2. Furthermore, SNPs in IL17A, ICA1, PKN1 and SNPs in the NF-κB pathway genes CARD8, IKBKE and TANK were found suggestively associated with GC-like structures.ConclusionsOur findings suggest that genetic variations may explain why ectopic GC-like structures are present in some pSS patients, and support the hypothesis that GC+ and GC− patients represent distinct disease phenotypes.
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