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- Li, He, et al.
(författare)
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Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:6
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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.
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| 7. |
- Salminen, M, et al.
(författare)
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Prediction of the Future Need for Institutional Care in Finnish Older People: A Comparison of Two Birth Cohorts
- 2018
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Ingår i: Gerontology. - : S. Karger AG. - 1423-0003 .- 0304-324X. ; 64:1, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> More recent birth cohorts of older people have better physical and cognitive status than earlier cohorts. As such, this could be expected to diminish the need for institutional care. The prediction of the future need for institutional care provides essential information for the planning and delivery of future care and social services as well as the resources needed. <b><i>Objective:</i></b> To predict the future need for institutional care among older Finnish people born in 1940. <b><i>Methods:</i></b> Representative samples of home-dwelling 70-year-olds from Turku, Finland were examined with similar methods in 1991 (those born in 1920) (<i>n</i> = 1,032) and in 2011 (those born in 1940) (<i>n</i> = 956). Predictors of institutionalization rates from the earlier 1920 cohort, together with data of sociodemographic factors, health, psychosocial and physical status, the need for help, and health behavior, were used to predict the future institutionalization rate among the 1940 cohort in this study using Cox regression models. <b><i>Results:</i></b> Health as well as psychosocial and physical status were significantly better in the 1940 cohort compared to the earlier cohort. In the 1940 cohort, the predicted rates of institutionalization were 1.8, 10.4, and 26.0% at the ages of 80 (year 2020), 85 (year 2025), and 90 years (year 2030), respectively. At every age (80, 85, and 90 years), the predicted rates of institutionalization by Mini-Mental State Examination (MMSE) were about two-fold among those with MMSE scores 18-26 (3.0-38.8%) compared to those with scores 27-30 (1.6-23.7%) and those with a body mass index (BMI) <25 (2.5-34.3%) compared to those with a BMI of 25-29.9 (1.4-20.9%), and about three-fold among participants with several falls (5.3-57.0%) compared to participants with no falls (1.5-23.1%). <b><i>Conclusions:</i></b> The 1940 cohort performed better in health as well as psychosocial and physical status than the 1920 cohort. Nevertheless, the predicted rates of future need for institutional care were high, especially at the ages of 85 and 90 years, among those with a lowered cognitive or physical status.
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- Imgenberg-Kreuz, Juliana, et al.
(författare)
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Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature
- 2018
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 87:5
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Tidskriftsartikel (refereegranskat)abstract
- B cells play a key role in the pathogenesis of primary Sjogren's syndrome (pSS). The aim of this study was to analyse the transcriptome of CD19+ B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. RNA from purified CD19+ B cells from 12 anti-SSA antibody-positive untreated female patients with pSS and 20 healthy blood donors was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of <0.05 was applied to define differential gene expression. As validation, gene expression in B cells from 17 patients with pSS and 16 healthy controls was analysed using a targeted gene panel. RNA-sequencing identified 4047 differentially expressed autosomal genes in pSS B cells. Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. Among the top upregulated and validated genes were CX3CR1, encoding the fractalkine receptor involved in regulation of B-cell malignancies, CCL5/RANTES and CCR1. Increased expression of several members of the TNF superfamily was also identified; TNFSF4/Ox40L, TNFSF10/TRAIL, TNFSF13B/BAFF, TNFRSF17/BCMA as well as S100A8 and -A9/calprotectin, TLR7, STAT1 and STAT2. Among genes with downregulated expression in pSS B cells were SOCS1 and SOCS3, CD70 and TNFAIP3/A20. We conclude that B cells from patients with anti-SSA antibody-positive pSS display immune activation with upregulated expression of chemokines, chemokine receptors and a prominent type I and type II IFN signature, while suppressors of cytokine signalling are downregulated. This adds insight into the autoimmune process and suggests potential targets for future functional studies.
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- Chen, L., et al.
(författare)
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Risk of disability pension in patients following rectal cancer treatment and surgery
- 2015
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 102:11, s. 1426-1432
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAspects of survivorship, such as long-term ability to work, are increasingly relevant owing to the improved survival of patients with rectal cancer. The aim of this study was to assess risk and determinants of disability pension (DP) in this patient group. MethodsUsing Swedish national clinical and population-based registers, patients with stage I-III rectal cancer aged 18-61years in 1995-2009 were identified at diagnosis and matched with population comparators. Prospectively registered records of DP during follow-up were retrieved up to 2013. Non-proportional and proportional hazards models were used to estimate the incidence rate ratio (IRR) for DP annually and overall. Potential variations in risk by demographic and clinical factors were calculated, with relapse as a time-varying exposure. ResultsA total of 2815 patients were identified and compared with 13465 population comparators. During a median follow-up of 60 (range 0-10) years, 233 per cent of the relapse-free patients and 103 per cent of the population comparators received DP (IRR 240, 95 per cent c.i. 217 to 265). An increased annual risk of DP was evident almost every year until the tenth year of follow-up. Abdominoperineal resection was associated with an increased DP risk compared with anterior resection (IRR 144, 119 to 175). Surgical complications (IRR 133, 110 to 162) and reoperation (IRR 142, 109 to 184), but not radiotherapy or chemotherapy, were associated with risk of DP. ConclusionRelapse-free patients with rectal cancer of working age are at risk of disability pension. Higher than expected
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- Haworth, Simon, et al.
(författare)
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Consortium-based genome-wide meta-analysis for childhood dental caries traits
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:17, s. 3113-3127
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Tidskriftsartikel (refereegranskat)abstract
- Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortiumwide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.
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