| 1. |
- Appel, Silke, et al.
(författare)
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Potential association of muscarinic receptor 3 gene variants with primary Sjogren's syndrome
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 70:7, s. 1327-1329
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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.
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| 2. |
- Bolstad, Anne Isine, et al.
(författare)
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Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:6, s. 981-988
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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.
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| 3. |
- Dideberg, Vinciane, et al.
(författare)
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An insertion-deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:24, s. 3008-3016
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Tidskriftsartikel (refereegranskat)abstract
- The interferon regulatory factor 5 (IRF5) gene encodes a transcriptionfactor that plays an important role in the innate as well asin the cell-mediated immune responses. The IRF5 gene has beenshown to be associated with systemic lupus erythematosus andrheumatoid arthritis. We studied whether the IRF5 gene is alsoassociated with inflammatory bowel diseases (IBD), Crohn disease(CD) and ulcerative colitis (UC). Twelve polymorphisms in theIRF5 gene were genotyped in a cohort of 1007 IBD patients (748CD and 241 UC) and 241 controls from Wallonia, Belgium. Thesame polymorphisms were genotyped in a confirmatory cohort of311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven,Belgium. A strong signal of association (p = 1.9 x 10–5,OR: 1.81 (1.37-2.39)) with IBD was observed for a 5bp indel(CGGGG) polymorphism in the promoter region of the IRF5 gene.The association was detectable (p = 6.8 x 10–4) also inCD patients, and was particularly strong among the UC patients(p = 5.3 x 10–8, OR 2.42 (1.76 -3.34)). The associationof the CGGGG indel was confirmed in the second cohort (p = 3.2x 10–5, OR 1.59 (1.28 - 1.98)). The insertion of one CGGGGunit is predicted to create an additional binding site for thetranscription factor SP1. Using an electrophoretic mobilityshift assay we show allele-specific differences in protein bindingto this repetitive DNA-stretch, which suggest a potential functionrole for the CGGGG indel.
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| 4. |
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| 5. |
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| 6. |
- Isine Bolstad, Anne, et al.
(författare)
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Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:6, s. 981-988
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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.
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| 7. |
- Kristjansdottir, Gudlaug, et al.
(författare)
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Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
- 2008
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 45:6, s. 362-369
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
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| 8. |
- Kristjansdottir, Gudlaug Thora, 1972-
(författare)
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Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune response. The IRF5 gene has received considerable attention since it was shown to be associated with two autoimmune diseases; systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of this thesis was to examine if IRF5 is associated with other autoimmune diseases and to investigate the role of the genetic variation of IRF5. In the first study a set of common polymorphisms in IRF5 were analyzed for their association with two subgroup of inflammatory bowel disease (IBD); Crohn´s diseases (CD) and ulcerative colitis (UC). A strong signal of association of IRF5 with IBD was found. The most strongly associated polymorphism is a 5 base pair (bp) insertion-deletion (indel) in the promoter region of the IRF5 gene. The association was detected within both UC and CD, and appeared to be stronger in UC. In the second study we investigated the association of IRF5 with multiple sclerosis (MS). A similar set of polymorphisms as in the IBD study were genotyped in a cohort of MS patients and controls. The same polymorphisms that were associated with IBD were also found to be associated with MS. In the third study, we performed a comprehensive investigation of the IRF5 gene to detect most of the polymorphisms in the gene, and to determine to what extent they account for the association signals obtained from the gene. IRF5 was sequenced and 34 new polymorphisms were identified. Twenty seven of these, and 20 previously known SNPs in IRF5 were genotyped in an SLE case-control cohort. We found that only two polymorphisms, the 5bp indel and a SNP downstream of IRF5, account for the association signal from all the remaining markers in the IRF5 gene, and that these two polymorphisms are independently associated with SLE. Interestingly, in our studies on IBD and MS, we only observed the signal from the 5bp indel polymorphism as a risk factor for IBDs. In the fourth study the two independent risk alleles in IRF5, were tested for their association with primary Sjögren´s syndrome (pSS). In this study we also included one SNP in the STAT4 gene, since STAT4 had recently been shown to be associated with SLE. Both risk factors in IRF5 and STAT4 were found to be associated with pSS. The regulation of expression of IRF5 was also investigated in the first three studies. We observed allele-specific differences in protein binding as well as increased binding of the transcription factor SP1 to the 5bp risk allele. We also detected increased expression of the IRF5 mRNA from a promoter containing the risk allele. Taken together, the results of our studies suggest a general function for IRF5 as a regulator of the autoimmune response, where the 5bp indel is associated with IBD, MS, SLE and pSS. The additionally polymorphisms, which account for the remaining association signal obtained with SLE and pSS, may contribute to the disease manifestations that are specific for rheumatic diseases. Our studies add to the evidence that there are genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
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| 9. |
- Nordmark, Gunnel, et al.
(författare)
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Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome
- 2009
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:1, s. 68-76
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 × 10−9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.
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| 10. |
- Nordmark, Gunnel, et al.
(författare)
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Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome
- 2011
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 12:2, s. 100-109
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Tidskriftsartikel (refereegranskat)abstract
- We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10−5, OR 1.68, the family with sequence similarity 167 member A–B-lymphoid tyrosine kinase (FAM167A–BLK) locus, P=4.7 × 10−4, OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10−4, OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.
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