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Syvänen, Ann-Christine
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Publications (10 of 306) Show all publications
Leclair, V., Galindo-Feria, A. S., Rothwell, S., Krystufkova, O., Zargar, S. S., Mann, H., . . . Diaz-Galloc, L.-M. (2023). Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies. EBioMedicine, 96, Article ID 104804.
Open this publication in new window or tab >>Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
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2023 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 96, article id 104804Article in journal (Refereed) Published
Abstract [en]

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/).

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Autoantibody, HLA, Idiopathic inflammatory myopathy, Myositis
National Category
Rheumatology and Autoimmunity Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-516917 (URN)10.1016/j.ebiom.2023.104804 (DOI)001091791600001 ()37769433 (PubMedID)
Funder
European Science Foundation (ESF)
Available from: 2023-12-04 Created: 2023-12-04 Last updated: 2023-12-04Bibliographically approved
Rezayee, F., Eisfeldt, J., Skaftason, A., Ofverholm, I., Sayyab, S., Syvänen, A.-C., . . . Barbany, G. (2023). Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia. Frontiers in Oncology, 13, Article ID 1217712.
Open this publication in new window or tab >>Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia
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2023 (English)In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 13, article id 1217712Article in journal (Refereed) Published
Abstract [en]

Introduction The suitability of whole-genome sequencing (WGS) as the sole method to detect clinically relevant genomic aberrations in B-cell acute lymphoblastic leukemia (ALL) was investigated with the aim of replacing current diagnostic methods.

Methods For this purpose, we assessed the analytical performance of 150 bp paired-end WGS (90x leukemia/30x germline). A set of 88 retrospective B-cell ALL samples were selected to represent established ALL subgroups as well as ALL lacking stratifying markers by standard-of-care (SoC), so-called B-other ALL.

Results Both the analysis of paired leukemia/germline (L/N)(n=64) as well as leukemia-only (L-only)(n=88) detected all types of aberrations mandatory in the current ALLTogether trial protocol, i.e., aneuploidies, structural variants, and focal copy-number aberrations. Moreover, comparison to SoC revealed 100% concordance and that all patients had been assigned to the correct genetic subgroup using both approaches. Notably, WGS could allocate 35 out of 39 B-other ALL samples to one of the emerging genetic subgroups considered in the most recent classifications of ALL. We further investigated the impact of high (90x; n=58) vs low (30x; n=30) coverage on the diagnostic yield and observed an equally perfect concordance with SoC; low coverage detected all relevant lesions.

Discussion The filtration of the WGS findings with a short list of genes recurrently rearranged in ALL was instrumental to extract the clinically relevant information efficiently. Nonetheless, the detection of DUX4 rearrangements required an additional customized analysis, due to multiple copies of this gene embedded in the highly repetitive D4Z4 region. We conclude that the diagnostic performance of WGS as the standalone method was remarkable and allowed detection of all clinically relevant genomic events in the diagnostic setting of B-cell ALL.

Place, publisher, year, edition, pages
Frontiers Media SA, 2023
Keywords
B-cell acute lymphoblastic leukemia, whole-genome sequencing, genomic aberrations, diagnostic validation, class-defining genetic lesions
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-512192 (URN)10.3389/fonc.2023.1217712 (DOI)001059230800001 ()37664045 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationKnut and Alice Wallenberg Foundation, PR2019-0072Knut and Alice Wallenberg Foundation, PR 2022-00.76Knut and Alice Wallenberg Foundation, 2018-05661Swedish Research Council
Available from: 2023-09-28 Created: 2023-09-28 Last updated: 2024-01-17Bibliographically approved
Krali, O., Marincevic-Zuniga, Y., Arvidsson, G., Enblad, A. P., Lundmark, A., Sayyab, S., . . . Nordlund, J. (2023). Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia. npj Precision Oncology, 7(1), Article ID 131.
Open this publication in new window or tab >>Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia
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2023 (English)In: npj Precision Oncology, E-ISSN 2397-768X, Vol. 7, no 1, article id 131Article in journal (Refereed) Published
Abstract [en]

Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 281 B-cell precursor ALL (BCP-ALL) cases with previously undefined molecular phenotype, resulting in a single revised subtype for 81.5% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides a comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cancer and Oncology Hematology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-518188 (URN)10.1038/s41698-023-00479-5 (DOI)001118015800003 ()38066241 (PubMedID)
Funder
Uppsala University
Available from: 2023-12-18 Created: 2023-12-18 Last updated: 2024-01-15Bibliographically approved
Lundtoft, C., Pucholt, P., Martin, M., Bianchi, M., Lundström, E., Eloranta, M.-L., . . . Rönnblom, L. (2022). Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases. Arthritis & Rheumatology, 74(8), 1440-1450
Open this publication in new window or tab >>Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
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2022 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 74, no 8, p. 1440-1450Article in journal (Refereed) Published
Abstract [en]

Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogren's syndrome (SS), or myositis.

Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls.

Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 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.

Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-484681 (URN)10.1002/art.42122 (DOI)000815798000001 ()35315244 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationKarolinska InstituteSwedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondSwedish Society of MedicineRegion StockholmWallenberg Foundations
Available from: 2022-09-15 Created: 2022-09-15 Last updated: 2022-10-05Bibliographically approved
Carlsson Almlöf, J., Nystedt, S., Mechtidou, A., Leonard, D., Eloranta, M.-L., Grosso, G., . . . Syvänen, A.-C. (2021). Contributions of de novo variants to systemic lupus erythematosus. European Journal of Human Genetics, 29(1), 184-193
Open this publication in new window or tab >>Contributions of de novo variants to systemic lupus erythematosus
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2021 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 29, no 1, p. 184-193Article in journal (Refereed) Published
Abstract [en]

By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-422764 (URN)10.1038/s41431-020-0698-5 (DOI)000555535200001 ()32724065 (PubMedID)
Funder
Swedish Research Council
Available from: 2020-10-15 Created: 2020-10-15 Last updated: 2024-01-15Bibliographically approved
Imgenberg-Kreuz, J., Sandling, J. K., Norheim, K. B., Johnsen, S. J., Omdal, R., Syvänen, A.-C., . . . Nordmark, G. (2021). DNA Methylation-Based Interferon Scores Associate With Sub-Phenotypes in Primary Sjögren's Syndrome. Frontiers in Immunology, 12, Article ID 702037.
Open this publication in new window or tab >>DNA Methylation-Based Interferon Scores Associate With Sub-Phenotypes in Primary Sjögren's Syndrome
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2021 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 702037Article in journal (Refereed) Published
Abstract [en]

Primary Sjogren's syndrome (pSS) is an autoimmune inflammatory disease with profound clinical heterogeneity, where excessive activation of the type I interferon (IFN) system is considered one of the key mechanisms in disease pathogenesis. Here we present a DNA methylation-based IFN system activation score (DNAm IFN score) and investigate its potential associations with sub-phenotypes of pSS. The study comprised 100 Swedish patients with pSS and 587 Swedish controls. For replication, 48 patients with pSS from Stavanger, Norway, were included. IFN scores were calculated from DNA methylation levels at the IFN-induced genes RSAD2, IFIT1 and IFI44L. A high DNAm IFN score, defined as > mean(controls) +2SD(controls) (IFN score > 4.4), was observed in 59% of pSS patients and in 4% of controls (p=1.3x10(-35)). Patients with a high DNAm IFN score were on average seven years younger at symptom onset (p=0.017) and at diagnosis (p=3x10(-3)). The DNAm IFN score levels were significantly higher in pSS positive for both SSA and SSB antibodies compared to SSA/SSB negative patients (p(discovery)=1.9x10(-8), p(replication)=7.8x10(-4)). In patients positive for both SSA subtypes Ro52 and Ro60, an increased score was identified compared to single positive patients (p=0.022). Analyzing the discovery and replication cohorts together, elevated DNAm IFN scores were observed in pSS with hypergammaglobulinemia (p=2x10(-8)) and low C4 (p=1.5x10(-3)) compared to patients without these manifestations. Patients < 70 years with ongoing lymphoma at DNA sampling or lymphoma at follow-up (n=7), presented an increased DNAm IFN score compared to pSS without lymphoma (p=0.025). In conclusion, the DNAm-based IFN score is a promising alternative to mRNA-based scores for identification of patients with activation of the IFN system and may be applied for patient stratification guiding treatment decisions, monitoring and inclusion in clinical trials.

Place, publisher, year, edition, pages
Frontiers Media S.A.FRONTIERS MEDIA SA, 2021
Keywords
primary Sjogren's syndrome, interferon, DNA methylation, autoimmunity, interferonopathies, precision medicine
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-453050 (URN)10.3389/fimmu.2021.702037 (DOI)000679843300001 ()34335613 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, VR-MH Dnr 5212014-2263Swedish Research Council, Dnr 2018-02399Swedish Research Council, Dnr 2016-01982Swedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondSwedish Society of MedicineErik, Karin och Gösta Selanders FoundationM Borgströms stiftelse för ärftlighetsforskningScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2021-09-14 Created: 2021-09-14 Last updated: 2024-01-17Bibliographically approved
Reid, S., Hagberg, N., Sandling, J. K., Alexsson, A., Pucholt, P., Sjowall, C., . . . Leonard, D. (2021). Interaction between the STAT4rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 80(9), 1183-1189
Open this publication in new window or tab >>Interaction between the STAT4rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
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2021 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 9, p. 1183-1189Article in journal (Refereed) Published
Abstract [en]

Objective To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods Patients with SLE (n(discovery cohort)=776, n(replication cohort)=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0x10(-8)) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n= 45). Results In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.

Place, publisher, year, edition, pages
BMJ Publishing Group LtdBMJ, 2021
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-453080 (URN)10.1136/annrheumdis-2020-219727 (DOI)000686232600028 ()33766895 (PubMedID)
Funder
Swedish Research Council, D0283001
Note

Title in WoS: Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus

Available from: 2021-09-17 Created: 2021-09-17 Last updated: 2024-01-15Bibliographically approved
Sandling, J. K., Pucholt, P., Hultin-Rosenberg, L., Farias, F. H. G., Kozyrev, S. V., Eloranta, M.-L., . . . Rönnblom, L. (2021). Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. Annals of the Rheumatic Diseases, 80(1), 109-117
Open this publication in new window or tab >>Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
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2021 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 1, p. 109-117Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group LtdBMJ PUBLISHING GROUP, 2021
Keywords
autoimmunity, genetic, lupus erythematosus, polymorphism, systemic
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-434591 (URN)10.1136/annrheumdis-2020-218636 (DOI)000607296800028 ()33037003 (PubMedID)
Funder
Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Heart Lung FoundationSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2021-02-10 Created: 2021-02-10 Last updated: 2024-01-15Bibliographically approved
Sayyab, S., Lundmark, A., Larsson, M., Ringner, M., Nystedt, S., Marincevic-Zuniga, Y., . . . Syvänen, A.-C. (2021). Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia. Scientific Reports, 11(1), Article ID 15988.
Open this publication in new window or tab >>Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 15988Article in journal (Refereed) Published
Abstract [en]

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

Place, publisher, year, edition, pages
Springer NatureNATURE PORTFOLIO, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-451740 (URN)10.1038/s41598-021-95109-0 (DOI)000684554100002 ()34362951 (PubMedID)
Funder
Swedish Cancer SocietySwedish Childhood Cancer Foundation, PR2019-0046, PR2017-0023 Funding Source: Medline
Available from: 2021-08-30 Created: 2021-08-30 Last updated: 2024-01-15Bibliographically approved
Bolin, K., Imgenberg-Kreuz, J., Leonard, D., Sandling, J. K., Alexsson, A., Pucholt, P., . . . Nordmark, G. (2021). Variants in BANK1 are associated with lupus nephritis of European ancestry.. Genes and Immunity, 22(3), 194-202
Open this publication in new window or tab >>Variants in BANK1 are associated with lupus nephritis of European ancestry.
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2021 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 22, no 3, p. 194-202Article in journal (Refereed) Published
Abstract [en]

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10-4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10-7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
National Category
Rheumatology and Autoimmunity Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-464314 (URN)10.1038/s41435-021-00142-8 (DOI)000661397000001 ()34127828 (PubMedID)
Available from: 2022-01-13 Created: 2022-01-13 Last updated: 2024-01-15Bibliographically approved
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