| 1. |
- Kottyan, Leah C., et al.
(författare)
-
The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
-
Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
|
|
| 2. |
|
|
| 3. |
- Lessard, Christopher J., et al.
(författare)
-
Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome
- 2013
-
Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA. - 1061-4036 .- 1546-1718. ; 45:11, s. 1284-
-
Tidskriftsartikel (refereegranskat)abstract
- Sjogrens syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta andlt; 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogrens syndrome.
|
|
| 4. |
- Li, He, et al.
(författare)
-
Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
- 2017
-
Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:6
-
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.
|
|
| 5. |
|
|
| 6. |
- Seror, Raphaèle, et al.
(författare)
-
EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide.
- 2015
-
Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 1:1, s. 000022-000022
-
Forskningsöversikt (refereegranskat)abstract
- The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS.
|
|
| 7. |
- Seror, Raphaele, et al.
(författare)
-
Validation of EULAR primary Sjogren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)
- 2014
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:5, s. 859-866
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjogren's syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjogren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r= 0.59; ESSRPI with PGA: r= 0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.
|
|
