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Almlöf, Jonas Carlsson
Alternative names
Publications (10 of 19) Show all publications
Almlöf, J. C., Nystedt, S., Leonard, D., Eloranta, M.-L., Grosso, G., Sjowall, C., . . . Syvänen, A.-C. (2019). Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus. Human Genetics, 138(2), 141-150
Open this publication in new window or tab >>Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
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2019 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-378191 (URN)10.1007/s00439-018-01966-7 (DOI)000458432800003 ()30707351 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, D0283001Swedish Research Council, 2017-02000Swedish Research CouncilThe King Gustaf V's Jubilee FoundationSwedish Rheumatism Association
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-03-04Bibliographically approved
Imgenberg-Kreuz, J., Almlöf, J. C., Leonard, D., Alexsson, A., Nordmark, G., Eloranta, M.-L., . . . Sandling, J. K. (2018). DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 77(5), 736-743
Open this publication in new window or tab >>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed) Published
Abstract [en]

Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

Keywords
gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342164 (URN)10.1136/annrheumdis-2017-212379 (DOI)000430492600020 ()29437559 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, 521-2014-2263; 521-2013-2830; 521-2014-3954; 2016-01982; 350-2012-256AstraZenecaSwedish Society for Medical Research (SSMF)Swedish Rheumatism AssociationThe King Gustaf V's Jubilee FoundationSwedish Heart Lung FoundationStockholm County CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-06-19Bibliographically approved
Imgenberg-Kreuz, J., Leonard, D., Carlsson Almlöf, J., Rantapaa-Dahlqvist, S., Bengtsson, A., Jonsen, A., . . . Sandling, J. K. (2018). Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus. Scandinavian Journal of Rheumatology, 47, 3-3
Open this publication in new window or tab >>Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus
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2018 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 3-3Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-363887 (URN)000442295400005 ()
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Carlsson Almlöf, J., Alexsson, A., Imgenberg-Kreuz, J., Sylwan, L., Bäcklin, C., Leonard, D., . . . Syvänen, A.-C. (2017). Novel risk genes for systemic lupus erythematosus predicted by random forest classification. Scientific Reports, 7, Article ID 6236.
Open this publication in new window or tab >>Novel risk genes for systemic lupus erythematosus predicted by random forest classification
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-333524 (URN)10.1038/s41598-017-06516-1 (DOI)000406260100040 ()28740209 (PubMedID)
Funder
Swedish Research Council, 521-2014-2263, 521-2013-2830
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2017-11-14Bibliographically approved
Langefeld, C. D., Ainsworth, H. C., Graham, D. S. C., Kelly, J. A., Comeau, M. E., Marion, M. C., . . . Vyse, T. J. (2017). Transancestral mapping and genetic load in systemic lupus erythematosus. Nature Communications, 8, Article ID 16021.
Open this publication in new window or tab >>Transancestral mapping and genetic load in systemic lupus erythematosus
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16021Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-331233 (URN)10.1038/ncomms16021 (DOI)000405680100001 ()28714469 (PubMedID)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-02-19Bibliographically approved
Imgenberg-Kreuz, J., Almlöf, J. C., Leonard, D., Nordmark, G., Eloranta, M.-L., Padyukov, L., . . . Sandling, J. K. (2017). Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus. Arthritis & Rheumatology, 69(S10), Article ID 2654.
Open this publication in new window or tab >>Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 2654Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-346792 (URN)000411824106158 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Marzouka, N.-a., Nordlund, J., Bäcklin, C. L., Lönnerholm, G., Syvänen, A.-C. & Almlöf, J. C. (2016). CopyNumber450kCancer: baseline correction for accurate copy number calling from the 450k methylation array. Bioinformatics, 32(7), 1080-1082
Open this publication in new window or tab >>CopyNumber450kCancer: baseline correction for accurate copy number calling from the 450k methylation array
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2016 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 7, p. 1080-1082Article in journal (Refereed) Published
Abstract [en]

The Illumina Infinium HumanMethylation450 BeadChip (450k) is widely used for the evaluation of DNA methylation levels in large-scale datasets, particularly in cancer. The 450k design allows copy number variant (CNV) calling using existing bioinformatics tools. However, in cancer samples, numerous large-scale aberrations cause shifting in the probe intensities and thereby may result in erroneous CNV calling. Therefore, a baseline correction process is needed. We suggest the maximum peak of probe segment density to correct the shift in the intensities in cancer samples.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-296859 (URN)10.1093/bioinformatics/btv652 (DOI)000374236400016 ()26553913 (PubMedID)
Funder
Swedish Cancer Society, CAN2010/592Swedish Research Council, 90559401Swedish Foundation for Strategic Research , RBc08-008
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-11-28Bibliographically approved
Lindqvist, C. M., Lundmark, A., Nordlund, J., Freyhult, E., Ekman, D., Almlöf, J. C., . . . Syvänen, A.-C. (2016). Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. OncoTarget, 7(39), 64071-64088
Open this publication in new window or tab >>Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed) Published
Abstract [en]

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

Keywords
acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-310028 (URN)10.18632/oncotarget.11773 (DOI)000387167800099 ()27590521 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-08Swedish Cancer Society, CAN 2013/504Swedish Childhood Cancer Foundation, PR2014-0100Swedish Research Council, C0524801Knut and Alice Wallenberg Foundation
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
Imgenberg-Kreuz, J., Sandling, J. K., Almlöf, J. C., Nordlund, J., Signér, L., Norheim, K. B., . . . Nordmark, G. (2016). Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes. Annals of the Rheumatic Diseases, 75(11), 2029-2036
Open this publication in new window or tab >>Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes
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2016 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 11, p. 2029-2036Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.

METHODS: Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.

RESULTS: We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.

CONCLUSIONS: Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-278026 (URN)10.1136/annrheumdis-2015-208659 (DOI)000386469300023 ()26857698 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Society for Medical Research (SSMF), 521-2014-2263 521-2013-2830Swedish Research Council, 350-2012-256Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2017-11-30Bibliographically approved
Sandling, J. K., Imgenberg-Kreuz, J., Carlsson Almlöf, J., Nordmark, G., Eloranta, M.-L., Padyukov, L., . . . Syvänen, A.-C. (2015). Genome-wide analysis of DNA methylation in systemic lupus erythematosus. Paper presented at 11th International Congress on Systemic Lupus Erythematosus, 2-6 September 2015, Vienna, Austria. Clinical and Experimental Rheumatology, 33(3), S74-S74
Open this publication in new window or tab >>Genome-wide analysis of DNA methylation in systemic lupus erythematosus
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2015 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 33, no 3, p. S74-S74Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-264928 (URN)000360421900266 ()
Conference
11th International Congress on Systemic Lupus Erythematosus, 2-6 September 2015, Vienna, Austria
Note

Supplement: 90, Meeting Abstract: P8.02

Available from: 2015-10-29 Created: 2015-10-19 Last updated: 2017-12-01Bibliographically approved
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