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- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
- 2022
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Ingår i: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8
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Tidskriftsartikel (refereegranskat)abstract
- Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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| 2. |
- Ekman, Diana, et al.
(författare)
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Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis
- 2023
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 62:9, s. 3213-3218
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
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| 4. |
- Olsson, H, et al.
(författare)
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Predictors of short- and long-term mortality in critically ill, older adults admitted to the emergency department : an observational study
- 2022
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Ingår i: BMC Emergency Medicine. - : Springer Nature. - 1471-227X .- 1471-227X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background In the future, we can expect an increase in older patients in emergency departments (ED) and acute wards. The main purpose of this study was to identify predictors of short- and long-term mortality in the ED and at hospital discharge. Methods This is a retrospective, observational, single-center, cohort study, involving critically ill older adults, recruited consecutively in an ED. The primary outcome was mortality. All patients were followed for 6.5-7.5 years. The Cox proportional hazards model was used. Results Regarding all critically ill patients aged >= 70 years and identified in the ED (n = 402), there was a significant association between mortality at 30 days after ED admission and unconsciousness on admission (HR 3.14, 95% CI 2.09-4.74), hypoxia on admission (HR 2.51, 95% CI 1.69-3.74) and age (HR 1.06 per year, 95% CI 1.03-1.09), (all p < 0.001). Of 402 critically ill patients aged >= 70 years and identified in the ED, 303 were discharged alive from hospital. There was a significant association between long-term mortality and the Charlson Comorbidity Index (CCI) > 2 (HR 1.90, 95% CI 1.46-2.48), length of stay (LOS) > 7 days (HR 1.72, 95% CI 1.32-2.23), discharge diagnosis of pneumonia (HR 1.65, 95% CI 1.24-2.21) and age (HR 1.08 per year, 95% CI 1.05-1.10), (all p < 0.001). The only symptom or vital sign associated with long-term mortality was hypoxia on admission (HR 1.70, 05% CI 1.30-2.22). Conclusions Among critically ill older adults admitted to an ED and discharged alive the following factors were predictive of long-term mortality: CCI > 2, LOS > 7 days, hypoxia on admission, discharge diagnosis of pneumonia and age. The following factors were predictive of mortality at 30 days after ED admission: unconsciousness on admission, hypoxia and age. These data might be clinically relevant when it comes to individualized care planning, which should take account of risk prediction and estimated prognosis.
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