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Lindblad-Toh, KerstinORCID iD iconorcid.org/0000-0001-8338-0253
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Publications (10 of 136) Show all publications
Eriksson, D., Dalin, F., Eriksson, G. N., Landegren, N., Bianchi, M., Hallgren, Å., . . . Kämpe, O. (2018). Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1. Journal of Clinical Endocrinology and Metabolism, 103(1), 179-186
Open this publication in new window or tab >>Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed) Published
Abstract [en]

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

National Category
Endocrinology and Diabetes Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343355 (URN)10.1210/jc.2017-01957 (DOI)000424934300021 ()29069385 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseEU, FP7, Seventh Framework Programme, 201167Stockholm County CouncilSwedish Society for Medical Research (SSMF)Swedish Society of MedicineNovo NordiskÅke Wiberg Foundation
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-04-24Bibliographically approved
Rohdin, C., Jäderlund, K. H., Ljungvall, I., Lindblad-Toh, K. & Häggstrom, J. (2018). High prevalence of gait abnormalities in pugs. The Veterinary Record, 182(6), Article ID 167.
Open this publication in new window or tab >>High prevalence of gait abnormalities in pugs
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2018 (English)In: The Veterinary Record, ISSN 0042-4900, E-ISSN 2042-7670, Vol. 182, no 6, article id 167Article in journal (Refereed) Published
Abstract [en]

The objective of this prospective study was to determine the prevalence of gait abnormalities in a cohort of Swedish pugs by using an owner-based questionnaire targeting signs of gait abnormality and video footage showing the dog's gait. This study also evaluated associated conditions of abnormal gait, including other health disorders prevalent in the breed. Five hundred and fifty (550) pugs registered in the Swedish Kennel Club, of one, five and eight years of age, in 2015 and 2016, were included in the study. Gait abnormalities were reported in 30.7 per cent of the responses. In the majority of cases, the character of the described gait indicated a neurological cause for the gait abnormality. An association was observed between abnormal gait and age, with gait abnormalities being significantly more common in older pugs (P=0.004). An association was also found between abnormal gait and dyspnoea, with dyspnoea being significantly more common in pugs with gait abnormalities (P<0.0001). This study demonstrated that the prevalence of gait abnormalities was high in the Swedish pug breed and increased with age. Future studies on the mechanisms behind these gait abnormalities are warranted.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2018
National Category
Other Veterinary Science
Identifiers
urn:nbn:se:uu:diva-348387 (URN)10.1136/vr.104510 (DOI)000425212900022 ()29437993 (PubMedID)
Available from: 2018-04-16 Created: 2018-04-16 Last updated: 2018-04-16Bibliographically approved
Broeckx, B. J. G., Derrien, T., Mottier, S., Wucher, V., Cadieu, E., Hedan, B., . . . Hitte, C. (2017). An exome sequencing based approach for genome-wide association studies in the dog. Scientific Reports, 7, Article ID 15680.
Open this publication in new window or tab >>An exome sequencing based approach for genome-wide association studies in the dog
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15680Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3'UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-342385 (URN)10.1038/s41598-017-15947-9 (DOI)000415266100029 ()29142306 (PubMedID)
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-02-22Bibliographically approved
Soda, T., Crowley, J., Breen, G., Bulik, C., Collier, S., Denny, J., . . . Sullivan, P. (2017). Biovupsych: Electronic Medical Record-Based Identification of Dna Samples for Disorders Under-Represented n The'Pgc. Paper presented at 23rd Annual World Congress of Psychiatric Genetics (WCPG), OCT 16-20, 2015, Toronto, CANADA. European Neuropsychopharmacology, 27, S243-S243
Open this publication in new window or tab >>Biovupsych: Electronic Medical Record-Based Identification of Dna Samples for Disorders Under-Represented n The'Pgc
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2017 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S243-S243Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-346579 (URN)000413843800271 ()
Conference
23rd Annual World Congress of Psychiatric Genetics (WCPG), OCT 16-20, 2015, Toronto, CANADA
Available from: 2018-03-21 Created: 2018-03-21 Last updated: 2018-03-21Bibliographically approved
Ardesjö-Lundgren, B., Tengvall, K., Bergvall, K., Farias, F. H. G., Wang, L., Hedhammar, Å., . . . Andersson, G. (2017). Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs. Veterinary dermatology (Print), 28(4), 377-e88
Open this publication in new window or tab >>Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs
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2017 (English)In: Veterinary dermatology (Print), ISSN 0959-4493, E-ISSN 1365-3164, Vol. 28, no 4, p. 377-e88Article in journal (Refereed) Published
Abstract [en]

Background - Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome-wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin-2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.

Objectives - The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD-affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.

Animals/Methods - Skin biopsies were collected from nine CAD-affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.

Results - We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.

Conclusion - Plakophilin-2 protein in dog skin is expressed in both epithelial and immune cells; based on Its sub cellular location its functional role is implicated in both nuclear and structural processes.

Place, publisher, year, edition, pages
WILEY, 2017
National Category
Veterinary Science
Identifiers
urn:nbn:se:uu:diva-333703 (URN)10.1111/vde.12441 (DOI)000407137900010 ()28386956 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826, 221-2009-1689, 524-2012-7053EU, European Research Council, 310203
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2017-11-21Bibliographically approved
Seelig, D. M., Ito, D., Forster, C. L., Yoon, U. A., Breen, M., Burns, L. J., . . . Linden, M. A. (2017). Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies. Leukemia and Lymphoma, 58(7), 1702-1710
Open this publication in new window or tab >>Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies
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2017 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 7, p. 1702-1710Article in journal (Refereed) Published
Abstract [en]

Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

Keyword
Diffuse large B-cell lymphoma, alternative NFκB pathway, canine model, comparative pathology, targeting therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-321317 (URN)10.1080/10428194.2016.1260122 (DOI)000399474000024 ()27931134 (PubMedID)
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2017-05-19Bibliographically approved
Meadows, J. & Lindblad-Toh, K. (2017). Dissecting evolution and disease using comparative vertebrate genomics. Nature reviews genetics, 18(10), 624-636
Open this publication in new window or tab >>Dissecting evolution and disease using comparative vertebrate genomics
2017 (English)In: Nature reviews genetics, ISSN 1471-0056, E-ISSN 1471-0064, Vol. 18, no 10, p. 624-636Article, review/survey (Refereed) Published
Abstract [en]

With the generation of more than 100 sequenced vertebrate genomes in less than 25 years, the key question arises of how these resources can be used to inform new or ongoing projects. In the past, this diverse collection of sequences from human as well as model and non-model organisms has been used to annotate the human genome and to increase the understanding of human disease. In the future, comparativevertebrate genomics in conjunction with additional genomic resources will yield insights into the processes of genome function, evolution, speciation, selection and adaptation, as well as the quantification of species diversity. In this Review, we discuss how the genomics of non-human organisms can provide insights into vertebrate biology and how this can contribute to the understanding of human physiology and health.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-342161 (URN)10.1038/nrg.2017.51 (DOI)000410808600004 ()28736437 (PubMedID)
Funder
Swedish Research Council Formas, 221-2012-1531Swedish Research CouncilEU, European Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-03-19Bibliographically approved
Wucher, V., Legeai, F., Hédan, B., Rizk, G., Lagoutte, L., Leeb, T., . . . Derrien, T. (2017). FEELnc: a tool for long non-coding RNA annotation and its application to the dog transcriptome. Nucleic Acids Research, 45(8), Article ID e57.
Open this publication in new window or tab >>FEELnc: a tool for long non-coding RNA annotation and its application to the dog transcriptome
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 8, article id e57Article in journal (Refereed) Published
Abstract [en]

Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.

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-321316 (URN)10.1093/nar/gkw1306 (DOI)000400578600002 ()28053114 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201370European Science Foundation (ESF)EU, European Research Council
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2017-05-30Bibliographically approved
Noh, H. J., Tang, R., Flannick, J., O'Dushlaine, C., Swofford, R., Howrigan, D., . . . Lindblad-Toh, K. (2017). Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nature Communications, 8, Article ID 774.
Open this publication in new window or tab >>Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 774Article in journal (Refereed) Published
Abstract [en]

Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 x 10(-11)) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-340126 (URN)10.1038/s41467-017-00831-x (DOI)000413116100001 ()29042551 (PubMedID)
Funder
Swedish Research Council, K2013-61P-22168NIH (National Institute of Health), 1R21MH109938-01
Note

Elinor K. Karlsson and Kerstin Lindblad-Toh contributed equally to this work

Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-02-01Bibliographically approved
Im, K. S., Graef, A. J., Breen, M., Lindblad-Toh, K., Modiano, J. F. & Kim, J.-H. (2017). Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma. Veterinary and Comparative Oncology, 15(2), 315-327
Open this publication in new window or tab >>Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma
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2017 (English)In: Veterinary and Comparative Oncology, ISSN 1476-5810, E-ISSN 1476-5829, Vol. 15, no 2, p. 315-327Article in journal (Refereed) Published
Abstract [en]

The CXCR4/CXCL12 axis plays an important role in cell locomotion and metastasis in many cancers. In this study, we hypothesized that the CXCR4/CXCL12 axis promotes migration and invasion of canine hemangiosarcoma (HSA) cells. Transcriptomic analysis across 12 HSA cell lines and 58 HSA whole tumour tissues identified heterogeneous expression of CXCR4 and CXCL12, which was associated with cell movement. In vitro, CXCL12 promoted calcium mobilization, cell migration and invasion that were directly proportional to surface expression of CXCR4; furthermore, these responses proved sensitive to the CXCR4 antagonist, AMD3100, in HSA cell lines. These results indicate that CXCL12 potentiates migration and invasion of canine HSA cells through CXCR4 signalling. The direct relationship between these responses in HSA cells suggests that the CXCR4/CXCL12 axis contributes to HSA progression.

Keyword
CXCL12, CXCR4, canine hemangiosarcoma, invasion, migration
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-321318 (URN)10.1111/vco.12165 (DOI)000401153000005 ()26337509 (PubMedID)
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2017-07-06Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8338-0253

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