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Rönnblom, Lars
Alternative names
Publications (10 of 169) 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
Idborg, H., Zandian, A., Ossipova, E., Wigren, E., Preger, C., Mobarrez, F., . . . Jakobsson, P.-J. (2019). Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.. Frontiers in Immunology, 10, Article ID 1029.
Open this publication in new window or tab >>Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed) Published
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10-9, 3 × 10-6, and 5 × 10-6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Keywords
Interferon regulating factor 5 (IRF5), SLE - Systemic Lupus Erythematous, antibody suspension bead arrays, biomarker discovery, hierarchical clustering, plasma proteomics, subgroups, unsupervised clustering
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-385062 (URN)10.3389/fimmu.2019.01029 (DOI)000468162000001 ()31156624 (PubMedID)
Funder
Swedish Research Council, 2017-02577Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Research Council, 2018-02000Stockholm County Council, 20160378Stockholm County Council, 20170038Swedish Rheumatism Association, R-748261Swedish Rheumatism Association, R-755861Swedish Rheumatism Association, R-753741Swedish Rheumatism Association, R-850611Swedish Rheumatism Association, R-739631Swedish Society of Medicine
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-11Bibliographically approved
Vasaitis, L., Nordmark, G., Theander, E., Backlin, C., Smedby, K. E., Askling, J., . . . Baecklund, E. (2019). Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome. Scandinavian Journal of Rheumatology, 48(3), 207-212
Open this publication in new window or tab >>Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome
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2019 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 3, p. 207-212Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

National Category
Rheumatology and Autoimmunity
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-366237 (URN)10.1080/03009742.2018.1523456 (DOI)000467940900005 ()30422723 (PubMedID)
Funder
Swedish Cancer SocietySwedish Rheumatism AssociationSwedish Society of MedicineThe King Gustaf V's Jubilee Foundation
Available from: 2018-11-18 Created: 2018-11-18 Last updated: 2019-06-18Bibliographically 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
Hagberg, N. & Rönnblom, L. (2019). Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T] [Letter to the editor]. Annals of the Rheumatic Diseases, 78(3), 429-431
Open this publication in new window or tab >>Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T]
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 3, p. 429-431Article in journal, Letter (Refereed) Published
Keywords
T cells, gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366407 (URN)10.1136/annrheumdis-2018-213836 (DOI)000471061000023 ()30269051 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-06-28Bibliographically approved
Crow, M. K. & Rönnblom, L. (2019). Type I interferons in host defence and inflammatory diseases. Lupus Science and Medicine, 6(1), Article ID e000336.
Open this publication in new window or tab >>Type I interferons in host defence and inflammatory diseases
2019 (English)In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 6, no 1, article id e000336Article, review/survey (Refereed) Published
Abstract [en]

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as 'friend' or 'foe', within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-390013 (URN)10.1136/lupus-2019-000336 (DOI)000471929000016 ()31205729 (PubMedID)
Funder
AstraZeneca
Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically 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
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