| 1. |
- Raffan, Eleanor, et al.
(författare)
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A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs
- 2016
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 23:5, s. 893-900
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Tidskriftsartikel (refereegranskat)abstract
- Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the b-MSH and beta-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.
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| 2. |
- Eriksson, D, et al.
(författare)
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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
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| 3. |
- Wilbe, Maria, et al.
(författare)
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Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease
- 2015
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAM-TOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.
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| 4. |
- Ahlgren, Kerstin M, et al.
(författare)
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Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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| 5. |
- Bianchi, Matteo, et al.
(författare)
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A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds-the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared similar to 167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
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| 6. |
- Tengvall, Katarina, et al.
(författare)
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Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:5, s. e1003475-
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Tidskriftsartikel (refereegranskat)abstract
- Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.
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| 7. |
- Truvé, Katarina, et al.
(författare)
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Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus
- 2016
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.
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| 8. |
- Jhamat, Naveed, et al.
(författare)
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Identification of Differentially Methylated Regions (DMR) in the genome of bovine endometrial epithelial cells (bEEC)challenged by E.Coli LPS and its effect on transcription
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Lipopolysaccharide (LPS) from Gram-negative bacteria induces the activation of pro-inflammatory pathways in the endometrium and such reactions potentially affect fertility and more specifically the implantation process. Gene expression studies based on RNA sequencing [Guo et al., Epiconcept Conference 2015, Abstract O-23, 34p] have shown that more than 2000 genes were differentially expressed (DEGs) in bEEC exposed to LPS. This study aimed to identify epigenetic correlates of these DEGs by detecting Differentially Methylated Regions (DMRs) in same cells. bEEC were exposed in vitro to 0, 2, and 8 μg/ml LPS for 24 hours. DNA libraries were prepared at The Babraham Institute, UK for reduced representation bisulfite sequencing (RRBS) using MspI digestion followed by end-repair/A-tailing and 5mC adaptor ligation and bisulfite conversion plus PCR. Sequences were analyzed using BS-Seeker2 for alignment of reads and MethylKit v0.9.5 for finding significant DMRs. AliBaba2 was used to predict potential transcription factor binding sites (TFBS) at DMRs using the TRANSFAC database. Analysis of RRBS data revealed 78 DMRs with q-value<0.05 between controls and 2 μg/ml LPS samples (34 hyper- and 44 hypo-methylated) and 109 DMRs between controls and 8 μg/ml LPS samples (47 hyper- and 62 hypo-methylated). 17 common DMRs (in 2 μg/ml and 8μg/ml LPS groups vs. controls) were identified. A reciprocal relationship was found between methylation and gene expression data for a sub-set of loci known to be key regulators of endometrial function. For example, LIF (Leukemia Inhibitory Factor) gene was found to contain a hypo-methylated DMR and its expression was up-regulated. Predicted binding sites in this DMR have 100% conservation and gene synteny in the human genome. These analyses allow the identification of regions harbouring candidates for key regulatory elements of endometrial function, thus contributing to the understanding of LPS-induced deregulation that may impact implantation.
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| 9. |
- Zubair, Saima, et al.
(författare)
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Genome sequence of Streptococcus agalactiae strain 09mas018883, isolated from a Swedish cow
- 2013
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Ingår i: Genome Announcements. - 2169-8287. ; 1, s. 1-2
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Tidskriftsartikel (refereegranskat)abstract
- We announce the complete genome sequence of Streptococcus agalactiae strain 09mas018883, isolated from the milk of a cow with clinical mastitis. The availability of this genome may allow identification of candidate genes, leading to discovery of antigens that might form the basis for development of a vaccine as an alternative means of mastitis control.
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| 10. |
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