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Rönnblom, Lars
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Publications (10 of 166) Show all publications
Farias, F. H. G., Dahlqvist, J., Kozyrev, S. V., Leonard, D., Wilbe, M., Abramov, S., . . . Lindblad-Toh, K. (2019). A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. European Journal of Human Genetics, 27, 432-441
Open this publication in new window or tab >>A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-368313 (URN)10.1038/s41431-018-0297-x (DOI)000458626500013 ()30459414 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationKnut and Alice Wallenberg Foundation
Note

These authors contributed equally: Johanna Dahlqvist, Sergey V. Kozyrev, Dag Leonard, Maria Wilbe

Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2019-03-11Bibliographically approved
Allum, F., Hedman, A. K., Shaol, X., Cheung, W. A., Vijay, J., Guenard, F., . . . Grundberg, E. (2019). Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements. Nature Communications, 10, Article ID 1209.
Open this publication in new window or tab >>Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1209Article in journal (Refereed) Published
Abstract [en]

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-380447 (URN)10.1038/s41467-019-09184-z (DOI)000461161500005 ()30872577 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Morin, A., Madore, A.-M., Kwan, T., Ban, M., Partanen, J., Rönnblom, L., . . . Laprise, C. (2019). Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits. European Journal of Human Genetics, 27(1), 90-101
Open this publication in new window or tab >>Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 1, p. 90-101Article in journal (Refereed) Published
Abstract [en]

The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant-and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3'-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-373365 (URN)10.1038/s41431-018-0266-4 (DOI)000454111500012 ()30206357 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
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
Thorlacius, G. E., Wahren-Herlenius, M. & Rönnblom, L. (2018). An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome. Current Opinion in Rheumatology, 30(5), 471-481
Open this publication in new window or tab >>An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome
2018 (English)In: Current Opinion in Rheumatology, ISSN 1040-8711, E-ISSN 1531-6963, Vol. 30, no 5, p. 471-481Article, review/survey (Refereed) Published
Abstract [en]

Purpose of review Systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS) share several clinical and laboratory features, including an overexpression of type I interferon (IFN) regulated genes. The genetic background to this IFN signature and the role of the type I IFN system in the disease process have been partly clarified. Here, we summarize the latest information concerning the type I IFN system in both diseases. Recent findings A number of gene variants in the type I IFN signalling pathways associate with an increased risk for both SLE and pSS in several ethnicities. The function of some risk gene variants has been elucidated, as well as the importance of epigenetic changes in type I IFN regulated genes. MicroRNA-451 and miR-302d have been shown to target IFN regulatory factor 8 and 9, suggesting that noncoding RNAs can control the IFN system. A prominent type I IFN activation is related to several disease manifestations, and in SLE to a more severe disease phenotype. Phase II studies in SLE suggest beneficial effects of blocking the type I IFN receptor. Summary The activated type I IFN system in SLE and pSS has a strong genetic component, is important in the disease etiopathogenesis and can be targeted.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
genes, Sjogren's syndrome, systemic lupus erythematosus, therapy, type I interferon
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-363867 (URN)10.1097/BOR.0000000000000524 (DOI)000442248600004 ()29889694 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2019-04-04Bibliographically approved
Yavuz, S. & Rönnblom, L. (2018). Biomarkers: to be or not to be.. Annals of the Rheumatic Diseases, Article ID annrheumdis-2018-214608.
Open this publication in new window or tab >>Biomarkers: to be or not to be.
2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, article id annrheumdis-2018-214608Article in journal (Refereed) Published
Keywords
autoimmune diseases, disease activity, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366412 (URN)10.1136/annrheumdis-2018-214608 (DOI)30415201 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-23Bibliographically approved
Eriksson, D., Bianchi, M., Landegren, N., Dalin, F., Skov, J., Hultin-Rosenberg, L., . . . Kampe, O. (2018). Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden. Scientific Reports, 8, Article ID 8395.
Open this publication in new window or tab >>Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed) Published
Abstract [en]

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-357556 (URN)10.1038/s41598-018-26842-2 (DOI)000433538800022 ()29849176 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 201167Swedish Research Council FormasKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseNovo NordiskMarianne and Marcus Wallenberg FoundationTore Nilsons Stiftelse för medicinsk forskningÅke Wiberg FoundationSwedish Rheumatism AssociationSwedish Society of Medicine
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-20Bibliographically approved
Hjorton, K., Hagberg, N., Israelsson, E., Jinton, L., Berggren, O., Sandling, J. K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Research & Therapy, 20, Article ID 238.
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, article id 238Article in journal (Refereed) Published
Abstract [en]

Background: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).

Methods: Plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.

Results: In healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).

Conclusions: The IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.

Keywords
HCQ, IRAK4, NK, SLE, pDC
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366403 (URN)10.1186/s13075-018-1702-0 (DOI)000448243100001 ()30355354 (PubMedID)
Funder
Swedish Rheumatism AssociationAstraZenecaSwedish Research CouncilSwedish Society of Medicine
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-08Bibliographically approved
Hjorton, K., Hagberg, N., Israelsson, E., Berggren, O., Sandling, J. K., Thorn, K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1268-1269
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1268-1269Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368669 (URN)10.1136/annrheumdis-2018-eular.6369 (DOI)000444351003561 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically 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
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