| 1. |
- Abelson, Anna-Karin, et al.
(författare)
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STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 68:11, s. 1746-1753
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
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| 2. |
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| 3. |
- Kozyrev, Sergey, et al.
(författare)
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Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:4, s. 1234-1241
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.
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| 4. |
- Kozyrev, Sergey V, et al.
(författare)
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Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:2, s. 211-216
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.
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| 5. |
- Linga Reddy, MV Prasad, 1978-
(författare)
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The Genetics of Systemic Lupus Erythematosus : The Specificity of IRF5 to SLE.
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.
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| 6. |
- Linga-Reddy, M. V. Prasad, et al.
(författare)
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A polymorphic variant in the MHC2TA gene is not associated with systemic lupus erythematosus
- 2007
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 70:5, s. 412-414
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Tidskriftsartikel (refereegranskat)abstract
- Single-nucleotide polymorphisms (SNPs) in the major histocompatibility complex class II transactivator (MHC2TA) gene encoding the class II transactivator have been associated with multiple sclerosis, rheumatoid arthritis, and myocardial infarction in the Swedish population. We used a case-control approach to investigate the prevalence of a relevant variant in Swedish systemic lupus erythematosus (SLE) cohorts to determine whether SLE shares the same MHC2TA susceptibility allele as the other diseases. No differences were observed between cases and control subjects at either the allele or genotype levels. Furthermore, no significant correlations were found when comparing different clinical and serological SLE phenotypes. This particular polymorphism rs3087456 of the MHC2TA gene does not appear to influence genetic susceptibility to SLE in the Swedish population. We conclude that our data support neither allelic nor genotype association between the MHC2TA SNP and SLE.
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| 7. |
- Linga Reddy, M. V. Prasad, et al.
(författare)
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Genetic association of IRF5 with SLE in Mexicans : higher frequency of the risk haplotype and its homozygozity than Europeans
- 2007
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 121:6, s. 721-727
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Tidskriftsartikel (refereegranskat)abstract
- The IRF5 gene was found to be strongly associated with SLE. We identified two functional polymorphisms and recently an insertion/deletion together with a tag SNP defining the risk haplotype in individuals of European ancestry. We now analyzed sets of Mexican patients with SLE. Three polymorphisms in the IRF5 gene were genotyped in two sets of Mexican individuals with SLE and controls as well as in families including a set of pediatric SLE patients. A set of healthy Mexican Indians was also typed. Genetic association with SLE was found for all three polymorphisms. The genetic association was very strong in the case–control analysis in both sets (for SNP rs2070197, combined P = 1.26 × 10−21) and in families (combined P = 0.000004). Compared to healthy individuals with European ancestry, the frequency of the risk haplotype in healthy Mexican individuals was significantly higher and even higher in the healthy Mexican Indian group. Further, a much higher frequency of the risk haplotype and of individual homozygote for it was found among Mexican SLE patients. The significantly higher frequency of homozygote individuals for the risk haplotype among Mexican SLE patients could be the result of genetic admixture, and suggests the possibility that IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients.
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| 8. |
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| 9. |
- Rueda, Blanca, et al.
(författare)
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Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:12, s. 3815-3819
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent findings suggest that interferon regulatory factor 5 (IRF-5) may play a crucial role in several cellular processes, including the transcription of genes for inflammatory cytokines. Two genetic variants of the IRF5 gene (rs2004640 in exon 1 and rs2280714 in the 3'-untranslated region) have been shown to exert functional modifications affecting IRF5 messenger RNA splicing and expression, and have been associated with genetic predisposition to systemic lupus erythematosus (SLE). The aim of this study was to analyze the possible contribution of the IRF5 gene to the predisposition to rheumatoid arthritis (RA). METHODS: Three case-control cohorts from Spain (724 RA patients and 542 healthy controls), Sweden (281 RA patients 474 healthy controls), and Argentina (284 RA patients and 286 healthy controls) were independently analyzed. Genotyping for IRF5 rs2004640 and rs2280714 was performed using a TaqMan 5' allele-discrimination assay. RESULTS: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls. Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA. CONCLUSION: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA.
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| 10. |
- Sánchez, Fabio O, et al.
(författare)
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IFN-Regulatory Factor 5 Gene Variants Interact with the Class I MHC Locus in the Swedish Psoriasis Population
- 2008
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 128:7, s. 1704-1709
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a multifactorial disease of the skin with significant comorbidities of the musculoskeletal and cardiovascular system, which affects 2-3% of the Caucasian population. Failure to regulate prolonged T-helper 1-mediated inflammation is central to psoriasis and is a feature shared with other inflammatory diseases. IFNs are important initiators/regulators of inflammation that among other things can affect the expression of the main genetic determinant in psoriasis, namely HLA-C. Externally administered IFN-alpha, as in patients treated for viral infections, and IFN-alpha produced by plasmacytoid dendritic cells is a known trigger of psoriasis. IFN gamma is characteristically increased in psoriasis lesions. Expression of IFNs is controlled by factors such as IFN-regulatory factor 5 (IRF5) whose polymorphic haplotypes were recently found to associate with increased risk of systemic lupus erythematosus (SLE). The hypothesis underlying this study was that polymorphisms in the IRF5 gene contribute to inadequate control of inflammation in psoriasis. This hypothesis was tested by comparing the distribution of genotypes and haplotypes at IRF5 derived from genotyping single-nucleotide polymorphisms (SNPs) rs2004640, rs2070197, rs10954213, and rs2280714 in psoriasis patients and population-matched controls from the Stockholm Psoriasis Cohort. Polymorphisms at IRF5 did not associate with psoriasis per se; however, an interaction with class I major histocompatibility complex (MHC) genes was found.
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