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| 2. |
- Henmyr, Viktor, et al.
(författare)
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Characterization of genetic variation in TLR8 in relation to allergic rhinitis
- 2015
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley-Blackwell. - 0105-4538 .- 1398-9995.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A previous investigation of all 10 TLR-genes for associations with allergic rhinitis (AR) detected a number of significant SNPs in the TLR8 locus. The associations indicated that an accumulation of rare variants could explain the signal. The present study therefore searches for rare variants in the TLR8 region and also investigates the reproducibility of previous SNP associations.METHODS: The TLR8 gene was re-sequenced in 288 AR patients from Malmö and the data was compared with publically available data. Seven previously AR-associated SNPs from TLR8 were analyzed for AR-associations in 422 AR patients and 859 controls from the BAMSE cohort. The associations detected in present and previous studies were compared.RESULTS: Sequencing detected 13 polymorphisms (3 promotor, 10 coding) among 288 AR patients. Four of the coding polymorphisms were rare (MAF <1%) and three of those were novel. Two coding polymorphisms were benign missense mutations and the rest were synonymous. Comparison with 1000Genomes and Exome Aggregation Consortium data revealed no accumulation of rare variants in the AR cases. The AR-association tests made using the BAMSE cohort yielded 5 P-values < 0.05. Tests of IgE-levels yielded 4 significant SNP associations to birch pollen. Comparing results between different populations revealed opposing risk alleles, different gender effects and response to different allergens in the different populations.CONCLUSIONS: Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveal contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR. This article is protected by copyright. All rights reserved.
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| 4. |
- Antoniou-Kourounioti, Rea L., et al.
(författare)
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Temperature Sensing Is Distributed throughout the Regulatory Network that Controls FLC Epigenetic Silencing in Vernalization
- 2018
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Ingår i: Cell systems. - : Elsevier BV. - 2405-4712. ; 7:6, s. 643-655
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Tidskriftsartikel (refereegranskat)abstract
- Many organisms need to respond to complex, noisy environmental signals for developmental decision making. Here, we dissect how Arabidopsis plants integrate widely fluctuating field temperatures over month-long timescales to progressively upregulate VERNALIZATION INSENSITIVE3 (VIN3) and silence FLOWERING LOCUS C (FLC), aligning flowering with spring. We develop a mathematical model for vernalization that operates on multiple timescales-long term (month), short term (day), and current (hour)-and is constrained by experimental data. Our analysis demonstrates that temperature sensing is not localized to specific nodes within the FLC network. Instead, temperature sensing is broadly distributed, with each thermosensory process responding to specific features of the plants' history of exposure to warm and cold. The model accurately predicts FLC silencing in new field data, allowing us to forecast FLC expression in changing climates. We suggest that distributed thermosensing may be a general property of thermoresponsive regulatory networks in complex natural environments.
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| 5. |
- Benson, Mikael, 1954, et al.
(författare)
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A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis.
- 2009
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 64:9, s. 1286-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. OBJECTIVE: To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. METHODS: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. RESULTS: Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. CONCLUSION: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.
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| 6. |
- Bryborn, M., et al.
(författare)
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CLC- a novel susceptibility gene for allergic rhinitis?
- 2010
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 65:2, s. 220-228
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Tidskriftsartikel (refereegranskat)abstract
- P>Background: Studies of the nasal lavage fluid proteome have previously identified proteins differently expressed in patients with symptomatic allergic rhinitis, e.g. S100A7, prolactin-inducible protein (PIP), wingless-type MMTV integration site family, member 2B (WNT2B), Charcot-Leyden crystal protein (CLC) and palate lung nasal epithelial clone (PLUNC). The aim of the present study was to investigate if genetic variation associated with allergic rhinitis can be found in these genes. Methods: Peripheral blood was collected from 251 patients with birch and/or grass pollen-induced allergic rhinitis and 386 nonatopic healthy controls. A total of 39 single nucleotide polymorphisms (SNPs) distributed over the genes PIP, WNT2B, CLC and PLUNC were selected from dbSNP, genotyped and investigated for associations with allergic rhinitis. Twelve additional SNPs were subsequently analysed for CLC. Results: All 22 investigated SNPs in CLC were polymorphic. Ten SNPs yielded significant differences between cases and controls with respect to genotype frequencies. Homozygotes for the minor allele were more common in allergic individuals compared to healthy controls. The minor alleles of these SNPs were all located on the same haplotype. Furthermore, homozygotes for the minor allele of two of the promoter SNPs had higher average scores for birch in skin prick test. In contrast, for seven SNPs within the gene, heterozygotes and homozygotes for the major allele had higher average scores for grass. None of the other three genes showed association. Conclusion: Genetic variation in CLC was found to be associated with allergic rhinitis. The pattern of variation is compatible with a recessive inheritance model and the previously observed altered protein levels detected in patients with allergic rhinitis.
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| 7. |
- Cunningham, Janet L., et al.
(författare)
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Experiences in implementing immunopsychiatry in real life
- 2023
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Ingår i: Journal of Affective Disorders Reports. - : Elsevier. - 2666-9153. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Immunological mechanisms, both alone and in combination, are associated with a broad range of psychiatric disorders encompassing autoimmune, autoinflammatory disorders but also genetic, metabolic, or other immunological disorders. Early treatment improves the outcome for autoimmune disorders, but early diagnosis is more difficult when isolated psychiatric symptoms are manifestations of autoimmunity. Treatment of these cases must encompass integrated models of disease, as both systemic autoimmunity and psychological processes influence mental health. Several challenges need to be overcome to efficiently merge psychiatric and somatic disease paradigms and medical care ranging from language and conceptual barriers to organizational barriers. Since 2015, the Immunopsychiatry team at Uppsala University has developed a collaborative multidisciplinary approach to improve and integrate care for patients with moderate to severe psychiatric disorders. Based on this experience, we have outlined the obstacles to be overcome in taking steps forward to achieve the long-term goal of understanding and early detection and identification of treatable immunological conditions within the psychiatric patient population; the described framework of evaluations and work-flow may serve as a model for other centers.
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| 8. |
- Henmyr, Viktor, et al.
(författare)
-
Characterization of genetic variation in TLR8 in relation to allergic rhinitis
- 2015
-
Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995.
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A previous investigation of all 10 TLR-genes for associations with allergic rhinitis (AR) detected a number of significant SNPs in the TLR8 locus. The associations indicated that an accumulation of rare variants could explain the signal. The present study therefore searches for rare variants in the TLR8 region and also investigates the reproducibility of previous SNP associations. METHODS: The TLR8 gene was re-sequenced in 288 AR patients from Malmö and the data was compared with publically available data. Seven previously AR-associated SNPs from TLR8 were analyzed for AR-associations in 422 AR patients and 859 controls from the BAMSE cohort. The associations detected in present and previous studies were compared. RESULTS: Sequencing detected 13 polymorphisms (3 promotor, 10 coding) among 288 AR patients. Four of the coding polymorphisms were rare (MAF <1%) and three of those were novel. Two coding polymorphisms were benign missense mutations and the rest were synonymous. Comparison with 1000Genomes and Exome Aggregation Consortium data revealed no accumulation of rare variants in the AR cases. The AR-association tests made using the BAMSE cohort yielded 5 P-values < 0.05. Tests of IgE-levels yielded 4 significant SNP associations to birch pollen. Comparing results between different populations revealed opposing risk alleles, different gender effects and response to different allergens in the different populations. CONCLUSIONS: Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveal contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR. This article is protected by copyright. All rights reserved.
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| 9. |
- Henmyr, V., et al.
(författare)
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Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population
- 2017
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Variation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF≤1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients. Methods: Sanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data. Results: The overall level of genetic variation was clearly different among the 10 TLR genes. The TLR10-TLR1-TLR6 locus was the most variable, while the TLR7-TLR8 locus was consistently showing a much lower level of variation. The AR patients had a total of 37 promoter polymorphisms with 14 rare (MAF≤1%) and 14 AR-specific polymorphisms. These numbers were highly similar when comparing the AR and the European part of the 1000Genomes populations, with the exception of TLR10 where a significant (P=0.00009) accumulation of polymorphisms were identified. The coding sequences had a total of 119 polymorphisms, 68 were rare and 43 were not present in the European part of the 1000Genomes population. Comparing the numbers of rare and AR-specific SNPs in the patients with the European part of the 1000Genomes population it was seen that the numbers were quite similar both for individual genes and for the sum of all 10 genes. However, TLR1, TLR5, TLR7 and TLR9 showed a significant excess of rare variants in the AR population when compared to the non-Finnish European part of ExAC. In particular the TLR1 S324*nonsense mutation was clearly overrepresented in the AR population. Conclusions: Most TLR genes showed a similar level of variation between AR patients and public databases, but a significant excess of rare variants in AR patients were detected in TLR1, TLR5, TLR7, TLR9 and TLR10. This further emphasizes the frequently reproduced TLR10-TLR1-TLR6 locus as being involved in the pathogenesis of allergic rhinitis.
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| 10. |
- Hepworth, Jo, et al.
(författare)
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Absence of warmth permits epigenetic memory of winter in Arabidopsis
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Plants integrate widely fluctuating temperatures to monitor seasonal progression. Here, we investigate the temperature signals in field conditions that result in vernalisation, the mechanism by which flowering is aligned with spring. We find that multiple, distinct aspects of the temperature profile contribute to vernalisation. In autumn, transient cold temperatures promote transcriptional shutdown of Arabidopsis FLOWERING LOCUS C (FLC), independently of factors conferring epigenetic memory. As winter continues, expression of VERNALIZATION INSENSITIVE3 (VIN3), a factor needed for epigenetic silencing, is upregulated by at least two independent thermosensory processes. One integrates long-term cold temperatures, while the other requires the absence of daily temperatures above 15 °C. The lack of spikes of high temperature, not just prolonged cold, is thus the major driver for vernalisation. Monitoring of peak daily temperature is an effective mechanism to judge seasonal progression, but is likely to have deleterious consequences for vernalisation as the climate becomes more variable.
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