| 1. |
- 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.
|
|
| 2. |
- 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.
|
|
| 3. |
|
|
| 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. |
- Appel, Silke, et al.
(författare)
-
Potential association of muscarinic receptor 3 gene variants with primary Sjogren's syndrome
- 2011
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 70:7, s. 1327-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Primary Sjögren's syndrome (pSS) is characterised by a chronic inflammation of exocrine glands. Salivary gland infiltrates, however, do not correlate well with disease symptoms, and a primary role for the salivary gland parenchyma in disease development has been suggested. Specifically, dysfunction of exocrine pathways involving the muscarinic receptor 3 (CHRM3) has been indicated. Objective: To investigate possible genetic divergence in the CHRM3 gene in patients with pSS. Methods: 530 patients with pSS and 532 controls from a combined Swedish and Norwegian cohort were genotyped for 84 single nucleotide polymorphisms (SNPs) distributed throughout CHRM3. Results: Genetic association was observed with five SNPs localised in intron 3 and 4 of CHRM3, the strongest being rs7548522 (minor allele frequency = 0.06, OR=1.93, 95% CI (1.24 to 3.01); p=0.0033). In addition, clinical parameters, including focus score, abnormal Schirmer's test and presence of autoantibodies, were associated with different SNPs in CHRM3. Conclusion: The study demonstrates a novel association of CHRM3 polymorphisms with pSS, suggesting a functional role for CHRM3 and the salivary gland parenchyma in the pathogenesis of pSS.
|
|
| 6. |
- Bolstad, Anne Isine, et al.
(författare)
-
Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples
- 2012
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:6, s. 981-988
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Lymphotoxin β (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS.METHODS:527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing.RESULTS:Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS.CONCLUSIONS:A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Isine Bolstad, Anne, et al.
(författare)
-
Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples
- 2012
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:6, s. 981-988
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogrens syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin alpha (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. less thanbrgreater than less thanbrgreater thanMethods 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. less thanbrgreater than less thanbrgreater thanResults Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. less thanbrgreater than less thanbrgreater thanConclusions A strong association was found between several SNP in the LTA/LTB/TNF alpha locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.
|
|
| 10. |
- Koro, Catalin, et al.
(författare)
-
Carbamylation of immunoglobulin abrogates activation of the classical complement pathway
- 2014
-
Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 44:11, s. 3403-3412
-
Tidskriftsartikel (refereegranskat)abstract
- Post-translational modifications of proteins significantly affect their structure and function. The carbamylation of positively charged lysine residues to form neutral homoitrulline occurs primarily under inflammatory conditions through myeloperoxidase-dependent cyanate (CNO-) formation. We analyzed the pattern of human IgG(1) carbamylation under inflammatory conditions and the effects that this modification has on the ability of antibodies to trigger complement activation via the classical pathway. We found that the lysine residues of IgG(1) are rapidly modified after brief exposure to CNO-. Interestingly, modifications were not random, but instead limited to only few lysines within the hinge area and the N-terminal fragment of the CH2 domain. A complement activation assay combined with mass spectrometry analysis revealed a highly significant inverse correlation between carbamylation of several key lysine residues within the hinge region and N-terminus of the CH2 domain and the proper binding of C1q to human IgG(1) followed by subsequent complement activation. This severely hindered complement-dependent cytotoxicity of therapeutic IgG(1). The reaction can apparently occur in vivo, as we found carbamylated antibodies in synovial fluid from rheumatoid arthritis patients. Taken together, our data suggest that carbamylation has a profound impact on the complement-activating ability of IgG(1) and reveals a pivotal role for previously uncharacterized lysine residues in this process.
|
|
