| 1. |
- Lyons, Paul A, et al.
(författare)
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Genetically Distinct Subsets within ANCA-Associated Vasculitis
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:3, s. 214-223
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)
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| 2. |
- Damman, P., et al.
(författare)
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Effects of age on long-term outcomes after a routine invasive or selective invasive strategy in patients presenting with non-ST segment elevation acute coronary syndromes : A collaborative analysis of individual data from the FRISC II - ICTUS - RITA-3 (FIR) trials
- 2012
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Ingår i: Heart. - : BMJ Publishing Group. - 1355-6037 .- 1468-201X. ; 98:3, s. 207-213
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To perform a patient-pooled analysis of a routine invasive versus a selective invasive strategy in elderly patients with non-ST segment elevation acute coronary syndrome. Methods: A meta-analysis was performed of patientpooled data from the FRISC IIeICTUSeRITA-3 (FIR) studies. (Un)adjusted HRs were calculated by Cox regression, with adjustments for variables associated with age and outcomes. The main outcome was 5-year cardiovascular death or myocardial infarction (MI) following routine invasive versus selective invasive management. Results: Regarding the 5-year composite of cardiovascular death or MI, the routine invasive strategy was associated with a lower hazard in patients aged 65-74 years (HR 0.72, 95% CI 0.58 to 0.90) and those aged ≥75 years (HR 0.71, 95% CI 0.55 to 0.91), but not in those aged less than65 years (HR 1.11, 95% CI 0.90 to 1.38), p=0.001 for interaction between treatment strategy and age. The interaction was driven by an excess of early MIs in patients less than65 years of age; there was no heterogeneity between age groups concerning cardiovascular death. The benefits were smaller for women than for men (p=0.009 for interaction). After adjustment for other clinical risk factors the HRs remained similar. Conclusion: The current analysis of the FIR dataset shows that the long-term benefit of the routine invasive strategy over the selective invasive strategy is attenuated in younger patients aged less than65 years and in women by the increased risk of early events which seem to have no consequences for long-term cardiovascular mortality. No other clinical risk factors were able to identify patients with differential responses to a routine invasive strategy. Trial registration: http://www.controlled-trials.com/ISRCTN82153174 (ICTUS), http://www.controlled-trials.com/ISRCTN07752711 (RITA-3).
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| 3. |
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| 4. |
- Wit, J M., et al.
(författare)
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Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models
- 2013
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Ingår i: Hormone Research in Paediatrics. - : Karger. - 1663-2818 .- 1663-2826. ; 79:5, s. 257-270
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Forskningsöversikt (refereegranskat)abstract
- The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.
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