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- Sandling, Johanna K., et al.
(författare)
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Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:1, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
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- Steffensen, Rudi, 1961
(författare)
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Molecular genetics of human carbohydrate defined blood groups. Studies of the ABO and P blood group systems
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to explore the molecular genetics of the carbohydrate defined blood group ABO and P systems.The blood group ABO system is the clinically most significant system in transfusion medicine. Using modern molecular biology, a number of the ABO alleles have been characterized. The phenotypes associated with these alleles have been shown to be a consequence of point mutations or deletions leading to (presumed) inactive or partly inactive glycosyltransferases. At the onset of this project, analysis of the ABO genes was hindered by lack of knowledge of the genomic organisation. The first part of this study therefore deals with the genomic organisation of the coding region, which was found to span seven exons. During our studies a new blood group O allele, designated O2 was identified. This new allele has a different inactivation mechanism than previously identified O alleles.The second part of this study aimed at gaining insight into the molecular genetics of the P blood group system, which is the last of the carbohydrate defined blood group systems to be elucidated. Using modern bioinfomatics and data from the human genome resources a gene, homologous to a new a4GlcNAc-transferase located on chromosome 3p14.3, was identified, cloned and expressed. The novel gene encoded an enzyme with Pk activity and a single homozygous missense mutation M183K was found in six Swedish individuals with the rare p phenotype. The mutant gene was inactive confirming that this gene represented Pk synthase. Although the gene appears to colocalize on chromosome 22 with the previously P1 polymorphism, the expressed enzyme did not function as a P1 synthase. The implications for the P1 genotype are discussed.
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