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- Lundtoft, Christian, et al.
(författare)
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Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
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Tidskriftsartikel (refereegranskat)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
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- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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- Lundtoft, Christian, et al.
(författare)
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Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases.
- 2022
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. We asked if C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) or myositis.Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterised Scandinavian patients with SLE, pSS or myositis, and 1,251 healthy controls.A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the three diseases. The strongest association was detected for patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (OR=18.0; CI95% : 10.2-33.3), whereas a weaker association was seen for patients without SSA/SSB autoantibodies (OR=3.1; CI95% : 1.7-5.5). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes.We show that a low C4A copy number more strongly is associated with the autoantibody repertoire than with the clinically defined disease entities. These results may have implication for understanding the aetiopathogenetic mechanisms of systemic inflammatory autoimmune diseases, and for patient stratification when taking the genetic profile into account. This article is protected by copyright. All rights reserved.
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- Strid, Anna, et al.
(författare)
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Diets benefiting health and climate relate to longevity in northern Sweden
- 2021
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 114:2, s. 515-529
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diets combining adequate nutritional quality and low climate impact are highly needed for human and planet health. Objectives; We aimed to 1) evaluate nutrient density indexes' ability to predict mortality, and 2) assess the effects of diets varying in nutrient density and climate impact on total mortality. Methods: Dietary data from 49,124 women and 47,651 men aged 35-65 y in the population-based prospective study Vasterbotten Intervention Programme (Sweden) were used. Greenhouse gas emissions (GHGEs) were estimated using data from life cycle assessments. Fifteen variants of nutrient density indexes were evaluated and the index that best predicted mortality was used to estimate participants' nutrient density. GHGEs and nutrient density were adjusted for energy intakes. Total mortality risk was estimated by Cox proportional hazards models for 4 groups of women and men, respectively, i.e., higher nutrient density, lower climate impact (HNutr/LClim); higher nutrient density, higher climate impact (HNutr/HClim); lower nutrient density, lower climate impact (LNutr/LClim); and lower nutrient density, higher climate impact (LNutr/HClim-reference group). Results: NRF11.3, a Sweden-adapted variant of the Nutrient Rich Foods index, was identified to have the best ability to predict mortality in the study population. Median follow-up times for women and men were 16.0 and 14.7 y, respectively. For women a significantly lower mortality risk was found for HNutr/LClim (HR: 0.87; 95% CI: 0.79, 0.96; P = 0.008) and HNutr/HClim (HR: 0.87; 95% CI: 0.78, 0.97; P = 0.011) than for LNutr/HClim. Among men LNutr/LClim had a significantly higher mortality risk (HR: 1.10; 95% CI: 1.01, 1.21; P = 0.033) than LNutr/HClim. Conclusions: Diets beneficial for both health and climate are feasible and associated with lower mortality risk in women. Further studies are needed to understand how men may transition into diets that are more sustainable from a combined health and climate perspective.
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- Ward, Nicholas D., et al.
(författare)
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Enhanced Aquatic Respiration Associated With Mixing of Clearwater Tributary and Turbid Amazon River Waters
- 2019
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Ingår i: Frontiers in Earth Science. - : Frontiers Media S.A.. - 2296-6463. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- When water bodies with unique biogeochemical constituents mix together there is potential for diverse responses by aquatic microbial communities and associated ecosystem functions. Here we evaluate bulk respiration under varying mixtures of turbid Amazon River water and two lowland tributaries-the Tapajos and Xingu rivers-based on O-2 drawdown in dark rotating incubation chambers. Experiments containing 5, 17, 33, and 50% tributary water mixed with Amazon River water were performed for the Tapajos and Xingu rivers at three different rotation velocities (0, 0.22, and 0.66 m s(-1)) during the falling water period. Pseudo first order reaction coefficients (k'), a measure of respiration potential, ranged from -0.15 to -1.10 d(-1), corresponding to respiration rates from 1.0 to 8.1 mg O-2 L d(-1). k'-values consistently increased with the rate of chamber rotation, and also was generally higher in the tributary-mainstem mixtures compared to pure endmembers. For both the Tapajos and Xingu rivers, the 17% mixture of tributary water yielded maximal k'-values, which were up to 2.9 and 2.2 times greater than in the tributary endmembers, respectively. The 50% mixtures, on the other hand, did not result in large increases in k'. We hypothesize that enhanced respiration potential after mixing unique water is driven, in part, by microbial priming effects that have been previously identified on a molecular level for these rivers. The results of this study suggest that there may be an optimal mixture for priming effects to occur in terms of the relative abundance of "priming" and "primed" substrates.
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