| 1. |
- Hallberg, Pär, 1974-, et al.
(författare)
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SWEDEGENE : a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 20:4, s. 579-585
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Tidskriftsartikel (refereegranskat)abstract
- SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.
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| 2. |
- Orsmark-Pietras, Christina, et al.
(författare)
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Precision Diagnostics in Myeloid Malignancies : Development and Validation of a National Capture-Based Gene Panel
- 2024
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Ingår i: Genes Chromosomes and Cancer. - 1045-2257. ; 63:7
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Tidskriftsartikel (refereegranskat)abstract
- Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel-of-normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS-MGP as part of standard-of-care identified clinically significant genes as well as recurrent mutations in less well-studied genes. In conclusion, the GMS-MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture-based design, easy to update once new guidelines become available. The GMS-MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies.
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| 3. |
- Tamarit, Daniel, et al.
(författare)
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Functionally structured genome architectures in Lactobacillus – insights into their variability and evolution
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial genome architectures evolve in response to selective pressures on the interplay between replication and gene expression. Several genomes contain a higher fraction of genes coding for proteins involved in information processes near the origin of replication, which is thought to be due to selection for rapid growth. We recently described a novel type of genome architecture in Lactobacillus kunkeei (Tamarit, et al. 2015). In this genome, vertically inherited genes encoding proteins with roles in translation and replication have accumulated in the chromosomal half surrounding the terminus of replication, while species-specific genes, and genes encoding proteins with metabolic and transport functions have accumulated in the chromosomal half around the origin of replication. Here, we show that this pattern is present also in the closest relatives of L. kunkeei, and similar but not identical biased genome architectures are present in other groups within the Lactobacillaceae. Thus, the biased genome structure in L. kunkeei has emerged from an ancestral clustering of vertically inherited genes around the terminus of replication, while horizontally acquired genes have been inserted near the origin of replication. The genome bias has been lost independently in several groups due to insertions of mobile elements near the terminus of replication and/or major genome rearrangements. We propose chromosomal structuring in macrodomains in the Lactobacillaceae, and suggest that further exploration of its functional consequences and generality will provide valuable insights into the forces that shape genome organization in bacteria.
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| 4. |
- Zhou, Wei, et al.
(författare)
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Gene-based association analysis of a large patient cohort identifies potential genecandidates for atypical femur fractures
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background:Several small genetic association studies have been conducted for atypical femurfracture (AFF) without replication of results. We assessed previously implicated and novel genesassociated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES).Methods:We performed gene-based association analysis on 139 European AFF cases and 196 controlsmatched for bisphosphonate use. We tested all rare, protein-altering variants using both candidategene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs(uncorrected p-values < 0.01) were investigated in a Swedish whole-genome sequencing replicationstudy and assessed in 46 non-European cases.Results:In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-freeapproach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likelycandidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in thereplication analysis, albeit not statistically significant. Three SNPs associated with SORD expressionaccording to the GTEx portal, were in linkage disequilibrium (R2 ≥0.2) with a SNP previouslyreported in a genome-wide association study of AFF. The prevalence of carriers of variants for bothPLOD2 and SORD was higher in Asian versus European cases.Conclusions:While we did not identify genes enriched for damaging variants, we found suggestiveevidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findingsindicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The studyprovides a stepping-stone for future larger genetic studies of AFF.
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| 5. |
- Ås, Joel
(författare)
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Genomic Analysis of Adverse Drug Reactions
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adverse drug reactions (ADRs) pose a significant global challenge, leading to substantial costs, suffering, and even loss of life. Genetic factors can play a role in determining a patient's response to the drug treatments and predicting ADRs. While many genetic associations with ADRs have been identified, there are still numerous ADRs suspected to have genetic components.In Paper I, the collection and curation strategies for ADR cases in the Swedegene biobank are established, presenting a cohort of 2,550 ADR-cases. Paper II presents the association between genetic variations in human leukocyte antigen (HLA) genes and the development of pancreatitis as a response to azathioprine treatment in patients with Crohn's disease. Paper III reports on an international collaboration to investigate the genetic aetiology of atypical femur fractures (AFF) during bisphosphonate treatment. The study found that previously identified genetic variants did not replicate, and --- as the cohort is the largest of its kind --- provides valuable insights into common genetic factors of AFF. Paper IV examines the genetic associations with central nervous system (CNS) toxicity as an ADR to antimicrobial drugs, identifying correlations with three genes linked to suicide and schizophrenia, although the biological connection remains unclear. Finally, Paper V presents a methodology for the experimental design of ADR studies by analysing the known protein interactions of drugs and proteins associated with ADRs. This approach aims to mitigate the impact of competing genetic correlations by identifying common protein interactions to validate the inclusion of drugs and ADRs in the study. These interactions are then ranked based on importance to the selected drugs and ADRs and used to propose genetic targets of interest. Overall, the findings of these studies contribute to the understanding of genetic predispositions to ADRs and provide a novel approach for data-driven experimental design for phenotype and genetic target selection.
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| 6. |
- Ås, Joel, et al.
(författare)
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HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease
- 2022
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Ingår i: Clinical and Translational Science. - : John Wiley & Sons. - 1752-8054 .- 1752-8062. ; 15:5, s. 1249-1256
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Tidskriftsartikel (refereegranskat)abstract
- The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA-DQA1*02:01 and HLA-DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine-induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA-DQA1*02:01 and HLA-DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57-9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23-10.98], p = 0.0275). In a disease-specific analysis, the correlation was positive in patients with Crohn's disease versus matched controls (OR 9.27 [95% CI 1.86-46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07-6.74], p = 0.749). In patients with Crohn's disease, we estimated the conditional risk of carriers of HLA-DQA1*02:01-HLA-DRB1*07:01 to 7.3%, and the conditional risk of a non-carrier to 2.2%. We conclude that HLA-DQA1*02:01-HLA-DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn's disease.
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| 7. |
- Ås, Joel, et al.
(författare)
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Network-Based Analysis of Protein Interactions among Drugs and Adverse Reactions: Identifying Phenotype-Groupings and Key Genes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background:Adverse drug reactions (ADRs) present a significant healthcare challenge, leading to morbidity, hospitalizations, and even fatalities. Serious ADRs are in general infrequent, since drugs with a high risk-benefit ratio are rarely approved by the authorities.Genetic factors contribute to serious ADRs, driving pharmacogenomic research to investigate drug-ADR-genetic relationships. These relationships are, however, still largely unstudied due to the scarcity of cases. This scarcity, coupled with the multiple hypothesis problem of genetic studies, poses challenges for these studies. One approach is to group similar ADRs or drugs to bolster sample sizes. However, grouping of drugs and ADRs requires caution to avoid including biologically ill-fitting cases. The objective of our study is to cluster drugs and ADRs based on previous genetic associations and shared protein interactions to propose phenotype groups and genetic targets for investigation.Methods:We developed a Bayesian probability model to substantiate protein-protein interactions across different drugs or ADRs. Subsequently, these proximity values were utilised for spectral clustering to form phenotype-groups. Once obtained, the model was reformulated to rank shared proteins for each cluster.Results:Permutation analysis demonstrated high sensitivity in correctly clustering drugs into therapeutic groups (sensitivity 94-97%) - outperforming other proposed methods - and assigning ADRs to clusters (sensitivity 86%). The model's reformulation enabled the ranking of shared proteins within each cluster, revealing enrichment in KEGG pathways relevant to therapeutic classifications. Discussion:This method successfully replicated known therapeutic drug classifications with high sensitivity, using shared protein interactions among KEGG pathways associated with drug functions. Using the proximity score and spectral clustering we propose phenotype groups and genetic targets for investigations. However, further studies are needed to assess the method's utility for the selection of cases and for target identification in less homogeneous drug-ADR scenarios.
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| 8. |
- Ås, Joel, et al.
(författare)
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Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.
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| 9. |
- Ås, Joel, et al.
(författare)
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Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
- 2024
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.
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