| 1. |
- Leclair, Valerie, et al.
(författare)
-
Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
- 2023
-
Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 96
-
Tidskriftsartikel (refereegranskat)abstract
- Background In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or-associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl,-Mi2,-Jo1,-Jo1/Ro52,-TIF1 gamma or negative for all analysed autoantibodies. Associations with HLA-DRB1*11, HLA-DRB1*15, HLA-DQA1*03, and HLA-DQB1*03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1*03, HLA-DQA1*05, and HLA-DQB1*02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/ Ro52-dominated subgroups. HLA-DRB1*16, HLA-DRB1*07 alleles were most frequent in anti-Mi2 and HLA- DRB1*01 and HLA-DRB1*07 alleles in the anti-TIF1 gamma subgroup. The HLA-DRB1*13, HLA-DQA1*01 and HLA-DQB1*06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1 gamma, and the negative subgroup. Interpretation Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. Funding See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript. Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
|
|
| 2. |
- Bianchi, Matteo, et al.
(författare)
-
Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
- 2022
-
Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
|
|
| 3. |
- Lundtoft, Christian, et al.
(författare)
-
Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases.
- 2022
-
Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 74:8, s. 1440-1450
-
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.
|
|
| 4. |
- Andersson, Helena
(författare)
-
The role of subsoil properties for phosphorus leaching in agricultural soils
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phosphorus (P) leaching from agricultural land is a large contributor to eutrophication of many surface waters and the Baltic Sea. Better knowledge of P sorption and release in the subsoil could enable the development of effective mitigation strategies for P leaching. This thesis examined the impact of soil properties on P leaching from four Swedish agricultural soils (two clays, two sands), using intact soil columns extracted with (length 1.05 m) and without (length 0.77 m) topsoil. The role of the subsoil as a source or sink for P leaching was also investigated, and placement of quicklime (CaO) on top of the subsoil as a mitigation strategy for P leaching was evaluated. Leaching of dissolved reactive P (DRP) from subsoil lysimeters was 94% of that from full-length lysimeters in one of the clay soils, and 70% in the other. The higher contribution of the former clay subsoil was probably due to high P content deeper in the soil. Leaching of DRP was low from full-length and subsoil lysimeters (0.12 and 0.08 kg ha-1 yr-1, respectively) in one of the sandy soils, despite high topsoil P content, due to high P sorption capacity and low degree of P saturation in the subsoil. However, leaching of DRP was very high from full-length and subsoil lysimeters (3.33 and 3.29 kg ha-1 yr-1, respectively) from the other sandy soil with moderate topsoil P content, due to high P content and low P sorption capacity in the subsoil. These results indicate that the subsoil can function as both a source and sink for P leaching. Phosphorus leaching increased with increasing P content and DPS in subsoil and decreasing P sorption capacity in topsoil and subsoil, indicating that these parameters could be used for P leaching risk assessments. However, on soils with preferential flow in the subsoil, P leaching may be high despite high subsoil P sorption capacity. Hence, both chemical and physical properties of topsoil and subsoil must be considered in implementation of appropriate, cost-effective mitigation strategies for P loss reductions. Application of lime on top of the subsoil significantly reduced leaching of particulate P (PP) in both clay subsoils by 49 and 51%, respectively, compared with unlimed controls. This suggests that subsoil liming might be an appropriate method to reduce P leaching from clay soils.
|
|
| 5. |
|
|
| 6. |
|
|
