26 results on '"Elaine R. Nimmo"'
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2. Changes to serum sample tube and processing methodology does not cause Intra-Individual [corrected] variation in automated whole serum N-glycan profiling in health and disease.
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Nicholas T Ventham, Richard A Gardner, Nicholas A Kennedy, Archana Shubhakar, Rahul Kalla, Elaine R Nimmo, IBD-BIOM Consortium, Daryl L Fernandes, Jack Satsangi, and Daniel I R Spencer
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Medicine ,Science - Abstract
Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system.25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual.There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status.The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N-glycan profile when processed using an automated workstream. This has important implications for N-glycan biomarker discovery studies using different serum processing standard operating procedures.
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- 2015
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3. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis.
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Alexandra-Chloé Villani, Mathieu Lemire, Edouard Louis, Mark S Silverberg, Catherine Collette, Geneviève Fortin, Elaine R Nimmo, Yannick Renaud, Sébastien Brunet, Cécile Libioulle, Jacques Belaiche, Alain Bitton, Daniel Gaudet, Albert Cohen, Diane Langelier, John D Rioux, Ian D R Arnott, Gary E Wild, Paul Rutgeerts, Jack Satsangi, Séverine Vermeire, Thomas J Hudson, and Denis Franchimont
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Medicine ,Science - Abstract
The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene.MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p
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- 2009
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4. Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways.
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Charlie W Lees, William J Zacharias, Mark Tremelling, Colin L Noble, Elaine R Nimmo, Albert Tenesa, Jennine Cornelius, Leif Torkvist, John Kao, Susan Farrington, Hazel E Drummond, Gwo-Tzer Ho, Ian D R Arnott, Henry D Appelman, Lauri Diehl, Harry Campbell, Malcolm G Dunlop, Miles Parkes, Sarah E M Howie, Deborah L Gumucio, and Jack Satsangi
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Medicine - Abstract
BackgroundUlcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.Methods and findingsUsing a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.ConclusionsHH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
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- 2008
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5. DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population
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I. D. R. Arnott, Linda Smith, Elaine R. Nimmo, Jack Satsangi, Hazel E. Drummond, and Colin L. Noble
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Adult ,Male ,Letter ,Genotype ,Population ,Nod2 Signaling Adaptor Protein ,Single-nucleotide polymorphism ,Biology ,Inflammatory bowel disease ,Loss of heterozygosity ,Crohn Disease ,Gene Frequency ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Genotyping ,Allele frequency ,Genetics ,education.field_of_study ,Tumor Suppressor Proteins ,Inflammatory Bowel Disease ,Haplotype ,Gastroenterology ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Epistasis, Genetic ,Middle Aged ,medicine.disease ,Inflammatory Bowel Diseases ,digestive system diseases ,Phenotype ,Haplotypes ,Scotland ,Immunology ,Colitis, Ulcerative ,Female - Abstract
Introduction: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G→A substitution at nucleotide 113, was associated with susceptibility to Crohn’s disease (CD) whereas an extended haplotype A conferred protection. Aims: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population. Patients and methods: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system. Results: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15. Conclusions: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.
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- 2019
6. Genetics of inflammatory bowel disease: scientific and clinical implications
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Elaine R. Nimmo, Jack Satsangi, N.B Shah, and J Morecroft
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Genetics ,Genetic Markers ,medicine.medical_specialty ,Crohn's disease ,business.industry ,Concordance ,Gastroenterology ,Inheritance Patterns ,Intracellular Signaling Peptides and Proteins ,Nod2 Signaling Adaptor Protein ,Disease ,medicine.disease ,Inflammatory Bowel Diseases ,Inflammatory bowel disease ,Ulcerative colitis ,digestive system diseases ,Chromosome 16 ,Molecular genetics ,Pharmacogenomics ,Immunology ,medicine ,Humans ,business ,Carrier Proteins - Abstract
Considerable progress has been made in the last decade in studies of the genetics of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Epidemiological data, notably concordance rates in twin pairs and sibling pairs, have provided strong evidence for the importance of the genetic contribution, particularly in Crohn's disease. These observations provided the catalyst for laboratory-based studies of the molecular genetics of Crohn's disease and ulcerative colitis around the world. The complementary strategies of genome-wide scanning and candidate gene-directed studies have led to the identification of a number of genetic markers which appear to predict disease susceptibility and behaviour. The identification of the IBD1 gene on chromosome 16 as NOD-2 is unquestionably an important scientific discovery. Although many issues with respect to gene function and expression remain to be resolved there is great optimism that important clinical applications will directly result.
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- 2019
7. Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe
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J. van Limbergen, Niall Anderson, Jack Satsangi, Richard K Russell, Linda Smith, Malcolm G. Dunlop, Mikael Lördal, Charlie W. Lees, Hazel E. Drummond, Susan M. Farrington, I. D. R. Arnott, Gamal Mahdi, Lawrence T. Weaver, U. Sjöqvist, Paraic McGrogan, Peter M. Gillett, Leif Törkvist, W M Bisset, David C. Wilson, K. Hassan, and Elaine R. Nimmo
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Adult ,Male ,Adolescent ,Genotype ,Biology ,Inflammatory bowel disease ,Nod1 Signaling Adaptor Protein ,medicine ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Allele frequency ,Sweden ,Polymorphism, Genetic ,Haplotype ,Gastroenterology ,Case-control study ,Odds ratio ,Middle Aged ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,Phenotype ,Scotland ,Case-Control Studies ,Immunology ,Mutation ,Female ,Age of onset - Abstract
Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype–phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. Conclusions: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.
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- 2019
8. Investigation of NOD1/CARD4 variation in inflammatory bowel disease using a haplotype-tagging strategy
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Niall Anderson, Linda Smith, Elaine R. Nimmo, Hazel E. Drummond, David C. Wilson, Johan Van Limbergen, Ian D. Arnott, G. Davies, Jack Satsangi, and Richard K Russell
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Adult ,Male ,Adolescent ,Quantitative Trait Loci ,Population ,Nod2 Signaling Adaptor Protein ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Inflammatory bowel disease ,Crohn Disease ,Nod1 Signaling Adaptor Protein ,NOD2 ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Molecular Biology ,Genetics (clinical) ,Genetic association ,education.field_of_study ,Haplotype ,General Medicine ,medicine.disease ,digestive system diseases ,body regions ,Haplotypes ,Case-Control Studies ,Immunology ,Colitis, Ulcerative ,SNP array - Abstract
Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype, although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.3. We have assessed, in detail, the influence of germline NOD1/CARD4 variation on IBD susceptibility and phenotype in the Scottish population. Two thousand two hundred and ninety-six subjects, including 356 children with IBD, were involved in parallel case–control and family-based association studies. Nine tagging single-nucleotide polymorphisms (SNPs) were selected based on HapMap data spanning the whole of the NOD1/CARD4 gene. Our case–control SNP analysis was powered to detect an effect size with OR 1.5 for IBD and OR 1.6 for CD. No significant associations were observed between any of nine the NOD1/CARD4 SNPs studied and IBD, CD or ulcerative colitis (UC) (P > 0.05 for all). Haplotype case–control analysis was also negative (P > 0.05 in IBD, CD and UC). Multimarker transmission disequilibrium testing analysis was negative (P > 0.05 in IBD, CD and UC). NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility. This study represents the first application of a gene -wide haplotype-tagging approach to assess, in detail, the contribution of NOD1/CARD4 in IBD.
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- 2019
9. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease
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Natalie J. Prescott, Holm H. Uhlig, Alison Simmons, William G. Newman, Loukas Moutsianas, David C. Wilson, Sun-Gou Ji, John C. Mansfield, Christopher J. Hawkey, Graham A. Heap, Cathryn Edwards, Charlie W. Lees, Javier Gutierrez-Achury, James Lee, Nicholas A. Kennedy, Christopher A. Lamb, Jeffrey C. Barrett, Craig Mowat, Christopher G. Mathew, Jack Satsangi, Yang Luo, Daniel L. Rice, Carl A. Anderson, Paul Henderson, Ailsa Hart, Jeremy D. Sanderson, Tariq Ahmad, Elaine R. Nimmo, Mark Tremelling, Luke Jostins, Miles Parkes, and Katrina M. de Lange
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0301 basic medicine ,Integrins ,Quantitative Trait Loci ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Inflammatory bowel disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Allele ,ITGB8 ,Gene ,Alleles ,Genetic association ,Inflammation ,Inflammatory Bowel Diseases ,medicine.disease ,3. Good health ,030104 developmental biology ,030211 gastroenterology & hepatology ,Genome-Wide Association Study - Abstract
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
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- 2017
10. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
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Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders
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0301 basic medicine ,AAI12 ,Chemistry(all) ,SUSCEPTIBILITY LOCI ,Science ,Population ,General Physics and Astronomy ,Physics and Astronomy(all) ,OF-FUNCTION VARIANTS ,Inflammatory bowel disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,NUMBER ,medicine ,Ring finger ,IMPUTATION ,Allele ,education ,POPULATION ,RISK ,education.field_of_study ,Multidisciplinary ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,MUTATIONS ,General Chemistry ,ASSOCIATION ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,3. Good health ,Ubiquitin ligase ,Transport protein ,Transmembrane domain ,030104 developmental biology ,medicine.anatomical_structure ,RARE VARIANTS ,Immunology ,biology.protein ,Cancer research ,3111 Biomedicine ,INFLAMMATORY-BOWEL-DISEASE - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763
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- 2016
11. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
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Jerome I. Rotter, Elaine R. Nimmo, Jeffrey C. Barrett, Jacques Belaiche, Cynthia Sandor, Martine De Vos, Natalie J. Prescott, Mark J. Daly, André Van Gossum, Dan L. Nicolae, Alain Bitton, A. Hillary Steinhart, Christopher G. Mathew, Rhian Gwilliam, L. Philip Schumm, M. Michael Barmada, Panos Deloukas, Olivier Dewit, Severine Vermeire, Debby Laukens, Miguel Regueiro, Edouard Louis, Kent D. Taylor, Cécile Libioulle, Jonathan Marchini, Carl A. Anderson, Emily O. Kistner, Judy H. Cho, John D. Rioux, Simon Heath, Clive M. Onnie, Themistocles Dassopoulos, John C. Mansfield, Myriam Mni, Jack Satsangi, Mark Tremelling, Jean-Pierre Hugot, Hazel E. Drummond, Ramnik J. Xavier, Mark Lathrop, Michel Georges, Steven R. Brant, Lon R. Cardon, Miles Parkes, Jilur Ghori, Tariq Ahmad, Michael T. Murtha, Mark S. Silverberg, Stephan R. Targan, Suzannah Bumpstead, Ivo Gut, Todd Green, Derek P. Jewell, Richard H. Duerr, Denis Franchimont, Paul Rutgeerts, Anne M. Griffiths, Sarah Hansoul, Diana Zelenika, Sheila A. Fisher, and Lisa W. Datta
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Genetics ,education.field_of_study ,Genome, Human ,Population ,Quantitative Trait Loci ,Locus (genetics) ,Genome-wide association study ,Disease ,Biology ,Crohn Disease ,IRGM ,Humans ,Genetic Predisposition to Disease ,education ,ATG16L1 ,CDKAL1 ,Genetic association - Abstract
Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease ( a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.
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- 2016
12. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
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Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)
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endocrine system diseases ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Pilot Projects ,CCL3L1 ,SUSCEPTIBILITY ,Arthritis, Rheumatoid ,Diabetes mellitus genetics ,0302 clinical medicine ,Crohn Disease ,Gene Frequency ,DUPLICATIONS ,SCHIZOPHRENIA ,Disease ,Copy-number variation ,Oligonucleotide Array Sequence Analysis ,Genetics ,0303 health sciences ,Multidisciplinary ,PSORIASIS ,HERITABILITY ,LARGE-SCALE ,Nucleic Acid Hybridization ,Science & Technology - Other Topics ,Wellcome Trust Case Control Consortium ,Quality Control ,DNA Copy Number Variations ,General Science & Technology ,Single-nucleotide polymorphism ,COPY-NUMBER VARIATION ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,MD Multidisciplinary ,mental disorders ,Genetic predisposition ,Diabetes Mellitus ,SNP ,Humans ,Genetic Predisposition to Disease ,Allele frequency ,POLYMORPHISMS ,030304 developmental biology ,Genetic association ,Science & Technology ,MULTIDISCIPLINARY SCIENCES ,DELETION ,C431 Medical Genetics ,Case-Control Studies ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.
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- 2016
13. Copy number variation of scavenger-receptor cysteine-rich domains within DMBT1 and Crohn's disease
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Elaine R. Nimmo, Jack Satsangi, Colin Veal, Christopher G. Mathew, I. Vind, Peder Fode, Pia S. Munkholm, Edward J. Hollox, Natalie J. Prescott, John C. Mansfield, Paal Skyt Andersen, and Shamik Polley
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0301 basic medicine ,medicine.medical_specialty ,DNA Copy Number Variations ,Receptors, Cell Surface ,Biology ,Article ,03 medical and health sciences ,Crohn Disease ,Protein Domains ,Genetic linkage ,Molecular genetics ,Genetics ,medicine ,Humans ,Cysteine ,Copy-number variation ,Allele ,Gene ,Alleles ,Genetics (clinical) ,2. Zero hunger ,Innate immune system ,Tumor Suppressor Proteins ,Calcium-Binding Proteins ,Human genetics ,3. Good health ,DNA-Binding Proteins ,030104 developmental biology ,Case-Control Studies ,Knockout mouse - Abstract
Previous work has shown that the gene DMBT1, which encodes a large secreted epithelial glycoprotein known as salivary agglutinin, gp340, hensin or muclin, is an innate immune defence protein that binds bacteria. A deletion variant of DMBT1 has been previously associated with Crohn's disease, and a DMBT1(-/-) knockout mouse has increased levels of colitis induced by dextran sulphate. DMBT1 has a complex copy number variable structure, with two, independent, rapidly mutating copy number variable regions, called CNV1 and CNV2. Because the copy number variable regions are predicted to affect the number of bacteria-binding domains, different alleles may alter host-microbe interactions in the gut. Our aim was to investigate the role of this complex variation in susceptibility to Crohn's disease by assessing the previously reported association. We analysed the association of both copy number variable regions with presence of Crohn's disease, and its severity, on three case-control cohorts. We also reanalysed array comparative genomic hybridisation data (aCGH) from a large case-control cohort study for both copy number variable regions. We found no association with a linear increase in copy number, nor when the CNV1 is regarded as presence or absence of a deletion allele. Taken together, we show that the DMBT1 CNV does not affect susceptibility to Crohn's disease, at least in Northern Europeans.European Journal of Human Genetics advance online publication, 27 January 2016; doi:10.1038/ejhg.2015.280.
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- 2016
14. Genome-wide association study identifies eight loci associated with blood pressure
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Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)
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Hemodynamics ,Genome-wide association study ,Blood Pressure ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Diastole ,11 Medical and Health Sciences ,POPULATION ,Genetics ,Genetics & Heredity ,RISK ,0303 health sciences ,education.field_of_study ,Econometric and Statistical Methods: General ,CELL-DIFFERENTIATION ,biology ,Intracellular Signaling Peptides and Proteins ,Chromosome Mapping ,Steroid 17-alpha-Hydroxylase ,COMMON VARIANTS ,3. Good health ,DNA-Binding Proteins ,Europe ,Cardiovascular Diseases ,PUBLIC-HEALTH ,BARTTERS-SYNDROME ,Blood Pressure/genetics ,Cardiovascular Diseases/genetics ,Cardiovascular Diseases/physiopathology ,Cytochrome P-450 CYP1A2/genetics ,DNA-Binding Proteins/genetics ,Diastole/genetics ,European Continental Ancestry Group/genetics ,Fibroblast Growth Factor 5/genetics ,Genetic Variation ,Genome-Wide Association Study ,Humans ,India ,Methylenetetrahydrofolate Reductase (NADPH2)/genetics ,Open Reading Frames/genetics ,Phospholipase C delta/genetics ,Polymorphism, Single Nucleotide ,Proteins/genetics ,Steroid 17-alpha-Hydroxylase/genetics ,Systole/genetics ,Wellcome Trust Case Control Consortium ,Life Sciences & Biomedicine ,hypertension ,Fibroblast Growth Factor 5 ,Systole ,Population ,European Continental Ancestry Group ,METHYLENETETRAHYDROFOLATE REDUCTASE GENE ,Single-nucleotide polymorphism ,LOW-RENIN HYPERTENSION ,White People ,Article ,03 medical and health sciences ,Open Reading Frames ,Fibroblast growth factor-5 ,Cytochrome P-450 CYP1A2 ,Geneeskunde(GENK) ,education ,Methylenetetrahydrofolate Reductase (NADPH2) ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Genetic association ,genome-wide association ,Science & Technology ,MUTATIONS ,Proteins ,06 Biological Sciences ,POLYMORPHISM ,Blood pressure ,Methylenetetrahydrofolate reductase ,biology.protein ,biology.gene ,Phospholipase C delta ,Developmental Biology - Abstract
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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- 2009
15. Changes to Serum Sample Tube and Processing Methodology Does Not Cause Inter-Individual Variation in Automated Whole Serum N-Glycan Profiling in Health and Disease
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Nicholas T Ventham, Richard A Gardner, Nicholas A Kennedy, Archana Shubhakar, Rahul Kalla, Elaine R Nimmo, IBD-BIOM Consortium, Daryl L Fernandes, Jack Satsangi, and Daniel I R Spencer
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Adult ,Male ,Blood Specimen Collection ,Multidisciplinary ,lcsh:R ,Correction ,lcsh:Medicine ,Blood Proteins ,Middle Aged ,Inflammatory Bowel Diseases ,Polysaccharides ,Humans ,Female ,lcsh:Q ,lcsh:Science ,Biomarkers ,Blood Chemical Analysis ,Chromatography, High Pressure Liquid ,Glycoproteins - Abstract
Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system.25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual.There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status.The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N-glycan profile when processed using an automated workstream. This has important implications for N-glycan biomarker discovery studies using different serum processing standard operating procedures.
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- 2015
16. Inflammatory Bowel Disease Associates with Proinflammatory Potential of the Immunoglobulin G Glycome
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Nicholas T. Ventham, Elaine R. Nimmo, Gordan Lauc, Irena Trbojević Akmačić, Frano Vučković, Hazel E. Drummond, Malcolm G. Dunlop, Mislav Novokmet, Maja Pučić Baković, Jerko Štambuk, Nicholas A. Kennedy, Rahul Kalla, Jack Satsangi, Harry Campbell, Evropi Theodoratou, Olga Gornik, Jasminka Krištić, and Yurii S. Aulchenko
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Adult ,Male ,Glycosylation ,Original Basic Science Articles ,IgG glycans ,Inflammatory bowel disease ,Immunoglobulin G ,glycomics ,Pathogenesis ,inflammatory bowel disease ,Polysaccharides ,medicine ,Immunology and Allergy ,Humans ,ulcerative colitis ,Crohn's disease ,biology ,Gastroenterology ,Case-control study ,Odds ratio ,Middle Aged ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Glycome ,3. Good health ,Logistic Models ,Phenotype ,ROC Curve ,Case-Control Studies ,Immunology ,biology.protein ,Female ,Chromatography, Liquid - Abstract
Article first published online 17 April 2015. Supplemental Digital Content is Available in the Text., Background: Glycobiology is an underexplored research area in inflammatory bowel disease (IBD), and glycans are relevant to many etiological mechanisms described in IBD. Alterations in N-glycans attached to the immunoglobulin G (IgG) Fc fragment can affect molecular structure and immunological function. Recent genome-wide association studies reveal pleiotropy between IBD and IgG glycosylation. This study aims to explore IgG glycan changes in ulcerative colitis (UC) and Crohn's disease (CD). Methods: IgG glycome composition in patients with UC (n = 507), CD (n = 287), and controls (n = 320) was analyzed by ultra performance liquid chromatography. Results: Statistically significant differences in IgG glycome composition between patients with UC or CD, compared with controls, were observed. Both UC and CD were associated with significantly decreased IgG galactosylation (digalactosylation, UC: odds ratio [OR] = 0.71; 95% confidence interval [CI], 0.5–0.9; P = 0.01; CD: OR = 0.41; CI, 0.3–0.6; P = 1.4 × 10−9) and significant decrease in the proportion of sialylated structures in CD (OR = 0.46, CI, 0.3–0.6, P = 8.4 × 10−8). Logistic regression models incorporating measured IgG glycan traits were able to distinguish UC and CD from controls (UC: P = 2.13 × 10−6 and CD: P = 2.20 × 10−16), with receiver–operator characteristic curves demonstrating better performance of the CD model (area under curve [AUC] = 0.77) over the UC model (AUC = 0.72) (P = 0.026). The ratio of the presence to absence of bisecting GlcNAc in monogalactosylated structures was increased in patients with UC undergoing colectomy compared with no colectomy (FDR-adjusted, P = 0.05). Conclusions: The observed differences indicate significantly increased inflammatory potential of IgG in IBD. Changes in IgG glycosylation may contribute to IBD pathogenesis and could alter monoclonal antibody therapeutic efficacy. IgG glycan profiles have translational potential as IBD biomarkers.
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- 2015
17. The role of glycosylation in IBD
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Harry Campbell, Iain K. Pemberton, Nicholas A. Kennedy, Vito Annese, Dermot P.B. McGovern, Vlatka Zoldoš, Elaine R. Nimmo, Evropi Theodoratou, Igor Rudan, Gordan Lauc, Nicholas T. Ventham, Maja Pučić-Baković, Daniel Kolarich, Jack Satsangi, Manfred Wuhrer, and Daryl L. Fernandes
- Subjects
Glycan ,Glycosylation ,Immunoglobulin G ,chemistry.chemical_compound ,Polysaccharides ,medicine ,Animals ,Humans ,Colitis ,Intestinal Mucosa ,Inner mucus layer ,Mannan-binding lectin ,chemistry.chemical_classification ,Hepatology ,biology ,Mucin ,Gastroenterology ,Mucins ,Galactose ,medicine.disease ,Inflammatory Bowel Diseases ,carbohydrates (lipids) ,Mucus ,chemistry ,Immunology ,biology.protein ,inflammatory bowel disease ,glycosylation ,Glycoprotein - Abstract
A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
- Published
- 2014
18. The intermediate filament protein vimentin is a regulator of NOD2 activity
- Author
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Jeffrey C. Barrett, Jack Satsangi, Kenneth W. Simpson, Elaine R. Nimmo, Paul Henderson, David C. Wilson, Belgin Dogan, Dinesh C. Soares, and Craig Stevens
- Subjects
Immunoprecipitation ,Colon ,Nod2 Signaling Adaptor Protein ,Vimentin ,Polymorphism, Single Nucleotide ,Article ,chemistry.chemical_compound ,Crohn Disease ,NOD2 ,Intermediate Filament Protein ,Humans ,Frameshift Mutation ,Gene ,Withanolides ,Reporter gene ,biology ,HEK 293 cells ,Gastroenterology ,Epithelial Cells ,Molecular biology ,digestive system diseases ,HEK293 Cells ,chemistry ,Microscopy, Fluorescence ,Withaferin A ,Cancer research ,biology.protein ,Disease Susceptibility - Abstract
Objective Mutations in the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) gene remain the strongest genetic determinants for Crohn9s disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, the authors aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim with CD susceptibility. Design Coimmunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or a NOD2 frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor, withaferin A (WFA), to assess effects on NOD2 function using the nuclear factor-kappaB (NF-κB) reporter gene, green fluorescent protein-LC3-based autophagy, and bacterial gentamicin protection assays. International genome-wide association meta-analysis data were used to test for associations of single-nucleotide polymorphisms in Vim with CD susceptibility. Results The leucine-rich repeat domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin colocalised at the cell plasma membrane, and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation and muramyl dipeptide-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive Escherichia coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim . Conclusion Vimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. In addition, Vim is a candidate susceptibility gene for CD, supporting the functional data.
- Published
- 2012
19. Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways
- Author
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Malcolm G. Dunlop, Lauri Diehl, E. M. Sarah Howie, Mark Tremelling, Henry D. Appelman, Jack Satsangi, Hazel E. Drummond, Deborah L. Gumucio, Albert Tenesa, Colin L. Noble, Gwo-Tzer Ho, Harry Campbell, Susan M. Farrington, Miles Parkes, Leif Törkvist, Charlie W. Lees, William J. Zacharias, John Y. Kao, Elaine R. Nimmo, Jennine Cornelius, and D. R. Ian Arnott
- Subjects
Male ,Inflammatory bowel disease ,Mice ,0302 clinical medicine ,Oligonucleotide Array Sequence Analysis ,Medicine(all) ,0303 health sciences ,biology ,integumentary system ,Gastroenterology ,General Medicine ,Middle Aged ,Hedgehog signaling pathway ,3. Good health ,England ,030220 oncology & carcinogenesis ,Medicine ,Female ,Research Article ,Signal Transduction ,Patched ,Adult ,Colonic Disease ,Immunology ,Gastroenterology and Hepatology ,Polymorphism, Single Nucleotide ,Zinc Finger Protein GLI1 ,Proinflammatory cytokine ,03 medical and health sciences ,Germline mutation ,GLI1 ,medicine ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Hedgehog Proteins ,Genetic Testing ,Colitis ,Hedgehog ,Germ-Line Mutation ,030304 developmental biology ,Inflammation ,Sweden ,Gene Expression Profiling ,Inflammatory Bowel Disease ,Genetics and Genomics ,medicine.disease ,Inflammatory Bowel Diseases ,digestive system diseases ,Mice, Inbred C57BL ,Scotland ,biology.protein ,Transcription Factors - Abstract
Background Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis. Methods and Findings Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C→G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09–1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1+/lacZ mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1+/lacZ mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model. Conclusions HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD., Charlie Lees and colleagues identify a reduced-function variant of the hedgehog signaling pathway protein GLI1 that associates with inflammatory bowel disease, and investigate its role in a mouse model of colitis., Editors' Summary Background. Inflammatory bowel diseases (IBDs) are common disorders in which parts of the digestive tract become repeatedly or continuously inflamed. The immune system normally protects the body from entities it identifies as foreign, but in IBD it mistakenly recognizes gut tissue, and immune system cells accumulate in the lining of the bowel, which causes inflammation. There are two main types of IBD—Crohn's disease (CD), which mainly affects the small bowel, and ulcerative colitis (UC), which affects only the large bowel (colon). Both types tend to run in families and usually develop between the ages of 15 and 35 years. Symptoms—including diarrhea, abdominal cramps, and unexplained weight loss—can be mild or severe and the disease can develop slowly or suddenly. There is no cure for IBD except surgical removal of the affected part of the digestive tract. However, drugs that modulate the immune system (for example, corticosteroids) or that specifically inhibit “proinflammatory cytokines” (proteins made by the immune system that stimulate inflammation) are often helpful in reducing symptoms. Why Was This Study Done? Why the immune system becomes unbalanced in people with IBD is not clear but it is known that IBD is “polygenic,” that is, a disease caused by the combined actions of two or more inherited gene variants. Although UC and CD are clinically different diseases, they share several “susceptibility loci” (regions of the genome that harbor disease-associated gene variants), including the IBD2 locus. The identification of the actual gene within the IBD2 locus that is altered in people who are susceptible to IBD might provide new insights into what causes the immune imbalance in IBD and into how to treat the disease. In this study, the researchers test the hypothesis that a variant of a gene called GLI1, which lies in the IBD2 locus, is associated with IBD susceptibility. GLI1 encodes a transcription factor (a protein that regulates the production of proteins) that is a central component in the signaling pathway named for a protein called “hedgehog.” This pathway is involved in the development of many organs, including the digestive tract. What Did the Researchers Do and Find? The researchers used a technique called gene-wide haplotype tagging to look for inherited GLl1 variants in patients with IBD and in healthy people living in Scotland, England, and Sweden. A specific variant of the GLI1 gene, resulting in alteration of a single amino acid component of the GLI1 protein, was associated with IBD (particularly with UC) in both Scotland and England; the same variant was weakly associated with IBD in the Swedish population. The variant GLI1 protein was only half as active as the normal protein in a laboratory assay, and, consistent with this result, the expression of several components of the hedgehog signaling pathway was lower in colon samples taken from patients with UC than in samples taken from healthy individuals. Finally, Gli1+/lacZ mice (which express half the normal amount of Gli1 protein) developed severe intestinal inflammation more rapidly than wild-type mice when they were treated with dextran sodium sulfate (DSS), a chemical that induces acute (sudden) colitis. Cellular analysis revealed that myeloid cells (cells that sense and modify the inflammatory response) are direct targets of the hedgehog signaling pathway. Furthermore, the expression of several pro-inflammatory cytokines (in particular, one called IL-23) increased more markedly in the Gli1+/lacZ mice than in the wild-type mice after DSS treatment. What Do These Findings Mean? These findings suggest that the normal response of the mammalian gut to challenge with inflammatory substances involves hedgehog signaling through GLI1 and that reduced GLI1 function might be one trigger for IBD. More specifically, the human genetic studies identify a GLI1 variant that is associated with IBD (at least in certain north European populations), the laboratory experiments indicate that this GLI1 variant encodes a protein with reduced activity, and the animal studies show that a similar reduction in Gli1 activity is sufficient to heighten intestinal inflammatory responses. Although this last result needs to be confirmed in animal models of chronic colitis that more closely resemble human IBD, these findings suggest that drugs that modulate hedgehog signaling might be useful in the treatment of IBD. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050239. The MedlinePlus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish) MedlinePlus provides links to other information Crohn's disease and ulcerative colitis (in English and Spanish) The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis The UK National Health Service Direct Encyclopedia also provides information on Crohn's disease and on ulcerative colitis Wikipedia has a page on the hedgehog signaling pathway (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
- Published
- 2008
20. IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland
- Author
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K Hassan, Gail Davies, Elaine R. Nimmo, Paraic McGrogan, Richard K Russell, Lawrence T. Weaver, W M Bisset, Niall Anderson, David C. Wilson, L Smith, Hazel E. Drummond, Jack Satsangi, Peter M. Gillett, J. van Limbergen, and Gamal Mahdi
- Subjects
Interleukin-23 receptor ,Adolescent ,Nod2 Signaling Adaptor Protein ,Disease ,Inflammatory bowel disease ,Pathogenesis ,Immune system ,Crohn Disease ,Genetic linkage ,NOD2 ,Medicine ,Humans ,Genetic Predisposition to Disease ,Letters ,business.industry ,Transmission (medicine) ,Gastroenterology ,Receptors, Interleukin ,medicine.disease ,Inflammatory Bowel Diseases ,digestive system diseases ,Phenotype ,Scotland ,Immunology ,Colitis, Ulcerative ,business - Abstract
The discovery of NOD2/CARD15 as the first susceptibility gene in Crohn’s disease has contributed significantly to a fundamental change in the direction of basic research in inflammatory bowel disease (IBD), triggering renewed interest in the integrity of the innate immune response in IBD and appropriate orchestration of a subsequent adaptive immune response.1,2 More widely, in all complex diseases this finding in 2001 provided a much welcomed and needed proof of principle for non-parametric linkage analysis. Another study with major implications for the pathogenesis of Crohn’s disease as well as for investigation of all complex disorders has recently been published.3 The North American consortium performed an association study testing 308 332 markers spanning the entire genome in 567 patients with ileal Crohn’s disease and 571 controls of non-Jewish European ancestry. Of the three markers reported to retain significance after stringent Bonferroni correction, two were located in the NOD2/CARD15 gene. The third marker (rs11209026) was a non-synonymous variant in the interleukin-23 receptor (IL23R) gene on chromosome 1p31. Replication was obtained in the index paper in a Jewish ancestry case-control analysis of patients with Crohn’s disease by transmission disequilibrium testing in 883 families with offspring affected by IBD and in a combined case-control analysis …
- Published
- 2007
21. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease
- Author
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Elaine R. Nimmo, John C. Mansfield, Jack Satsangi, Hazel Drummond, Carlo Berzuini, Andrew Keniry, Fraser Cummings, Natalie J. Prescott, Cathryn M. Lewis, Miles Parkes, Francesca Bredin, Mark Tremelling, Rhian Gwilliam, Sheila A. Fisher, Christopher G. Mathew, Pannagiotis Deloukas, Jeremy D. Sanderson, Alastair Forbes, Derek P. Jewell, Lon Cardon, and Clive M. Onnie
- Subjects
Adult ,Male ,Interleukin-23 receptor ,Population ,Nod2 Signaling Adaptor Protein ,IL23R, interleukin 23 receptor ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Inflammatory bowel disease ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Risk Factors ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Allele frequency ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Hepatology ,Gastroenterology ,Case-control study ,Epistasis, Genetic ,Receptors, Interleukin ,Odds ratio ,SNP, single nucleotide polymorphism ,Inflammatory Bowel Diseases ,medicine.disease ,Clinical–Alimentary Tract ,CI, confidence interval ,Phenotype ,England ,Scotland ,Case-Control Studies ,Immunology ,Colitis, Ulcerative ,Female ,030211 gastroenterology & hepatology - Abstract
Background & Aims: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn’s disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15. Methods: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn’s disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using χ2 statistics, and subgroup association was sought. Results: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 × 10−12]; odds ratio, 0.38; 95% confidence interval, 0.29–0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55–0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15. Conclusions: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.
- Published
- 2007
22. Lack of association of the pregnane X receptor (PXR/NR1I2) gene with inflammatory bowel disease: parallel allelic association study and gene wide haplotype analysis
- Author
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Elaine R. Nimmo, Sarah K. Tate, Jack Satsangi, Nicole Soranzo, Albert Tenesa, Hazel E. Drummond, G.-T. Ho, and I. D. R. Arnott
- Subjects
Pregnane X receptor ,Receptors, Steroid ,Haplotype ,Gastroenterology ,Case-control study ,Pregnane X Receptor ,Single-nucleotide polymorphism ,Biology ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Inflammatory bowel disease ,Polymorphism, Single Nucleotide ,digestive system diseases ,Gene Frequency ,Haplotypes ,Immunology ,medicine ,Humans ,Letters ,Allele ,Allele frequency - Abstract
The pregnane X receptor gene (PXR/NR1I2) regulates an array of genes involved in the response to xenobiotics.1,2 Dysregulation of this gene may critically influence intestinal barrier defence and susceptibility to inflammatory bowel disease (IBD).3 Recent data from Ireland have suggested strong associations between polymorphisms within the PXR/NR1I2 gene and IBD. Dring et al performed a case control study involving 422 patients with IBD (185 ulcerative colitis (UC) and 237 (Crohn’s disease (CD)) and 350 healthy controls, using eight candidate polymorphisms in this gene.4 Highly significant associations were demonstrated with UC, CD, and IBD as a whole. This effect was most significant for the two individual single nucleotide polymorphisms (SNPs) in the promoter region of this gene; compared between the IBD cohort and controls, rs3814055/−23585 (p = 0.000008; odds ratio (OR) 1.62 (95% confidence interval (CI) 1.31–2.00)) and rs1523127/−24381 (p = 0.0002; OR 1.50 (95% CI 1.21–1.84)). We have critically re-evaluated the contribution of these allelic …
- Published
- 2006
23. Novel susceptibility genes in inflammatory bowel disease
- Author
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Elaine R. Nimmo, Jack Satsangi, Daniel R. Gaya, Colin L. Noble, and Richard K. Russell
- Subjects
Proteomics ,Candidate gene ,Genomics ,Disease ,Computational biology ,Review ,Biology ,Inflammatory bowel disease ,Pathogenesis ,Nod1 Signaling Adaptor Protein ,Two-Hybrid System Techniques ,medicine ,Humans ,Genetic Predisposition to Disease ,Adaptor Proteins, Signal Transducing ,Oligonucleotide Array Sequence Analysis ,Genetics ,Crohn's disease ,Chemokine CCL20 ,Proteomic Profiling ,Genome, Human ,Gastroenterology ,General Medicine ,Macrophage Inflammatory Proteins ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Immunity, Innate ,Toll-Like Receptor 4 ,Toll-Like Receptor 5 ,Chemokines, CC - Abstract
The inflammatory bowel disease, Crohn’s disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling, are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.
- Published
- 2006
24. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease
- Author
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Niall Anderson, K Hassan, Lawrence T. Weaver, Paraic McGrogan, Elaine R. Nimmo, Richard K. Russell, David C. Wilson, Peter M. Gillett, Jack Satsangi, W M Bisset, Gamal Mahdi, Hazel E. Drummond, and Colin L. Noble
- Subjects
Adult ,Hypersensitivity, Immediate ,Male ,medicine.medical_specialty ,Linkage disequilibrium ,Adolescent ,Genotype ,Organic Cation Transport Proteins ,Single-nucleotide polymorphism ,Growth ,Biology ,Gastroenterology ,Inflammatory bowel disease ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Crohn Disease ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Solute Carrier Family 22 Member 5 ,Allele frequency ,Anthropometry ,Symporters ,Haplotype ,Inflammatory Bowel Disease ,Case-control study ,Epistasis, Genetic ,Odds ratio ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Phenotype ,Case-Control Studies ,Immunology ,Colitis, Ulcerative ,Female - Abstract
Background and aims: The OCTN1 (SLC22A4 1672C→T) and OCTN2 (SLC22A5 −207G→C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease (CD), but their contribution in children has not been examined.Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls.Results: All SNPs were in strong linkage disequilibrium (D′ >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (pConclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.
- Published
- 2006
25. NOD2/CARD15 and the Paneth cell:another piece in the genetic jigsaw of inflammatory bowel disease
- Author
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Marian C Aldhous, Elaine R. Nimmo, and Jack Satsangi
- Subjects
Paneth Cells ,Nod2 Signaling Adaptor Protein ,Gene Expression ,Disease ,Biology ,medicine.disease_cause ,Inflammatory bowel disease ,Pathogenesis ,Defensins ,Anti-Infective Agents ,Crohn Disease ,NOD2 ,medicine ,Humans ,Genetic Predisposition to Disease ,Mutation ,Gastroenterology ,Intracellular Signaling Peptides and Proteins ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,Human genetics ,Immunity, Innate ,medicine.anatomical_structure ,Immunology ,Paneth cell ,Commentary ,Colitis, Ulcerative ,Carrier Proteins - Abstract
Expression of NOD2/CARD15 in the Paneth cell may be critical in the pathogenesis of Crohn’s disease The emergence and application of novel molecular techniques over the last decade has provided a needed catalyst to studies of the pathogenesis of the chronic inflammatory bowel diseases (IBD): Crohn’s disease (CD) and ulcerative colitis (UC). Successful development of genetically engineered models of intestinal inflammation has not only provided insight into the dysregulation of the mucosal immune system characteristic of IBD but has also emphasised the critical and complex role of the bacterial flora in establishing and maintaining chronic intestinal inflammation.1 These advances in understanding pathophysiology in turn have already led to novel therapeutic approaches.2,3 However, it is in studies of human genetics that landmark progress has been made, widely recognised not only within gastroenterology but also by investigators in all complex diseases.4 Genome wide scanning led initially to the identification of a number of susceptibility loci, the statistical evidence for which satisfy stringent criteria for definite linkage.5 The subsequent detection of the NOD2/CARD15 gene6–8 within the IBD1 linkage interval and the association of mutations within this gene with susceptibility to CD is widely regarded as the most stringent proof of principle for hypothesis free genome scanning in complex diseases. In the time that has elapsed since the discovery of NOD2/CARD15, the contribution of this gene in determining susceptibility and disease behaviour in IBD has received detailed examination. It is now clear that NOD2/CARD15 mutations are associated with susceptibility to CD but not UC.6 However, the contribution is subject to considerable ethnic and even regional variation. Whereas mutations may be carried by up to 50% of central Europeans with CD,9 these mutations are not present in Japanese10 or Afro-American11 patients. Even within Europe, …
- Published
- 2003
26. A Schizosaccharomyces pombe artificial chromosome large DNA cloning system
- Author
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Elaine R. Nimmo, Robin C. Allshire, and Dorothy J. D. Young
- Subjects
Yeast artificial chromosome ,Genetics ,biology ,Genetic Vectors ,DNA, Recombinant ,Cloning vector ,Chromosome Mapping ,P1-derived artificial chromosome ,Molecular cloning ,Cosmids ,biology.organism_classification ,Molecular biology ,Transformation, Genetic ,Plasmid ,Schizosaccharomyces ,Schizosaccharomyces pombe ,Humans ,Genomic library ,Cloning, Molecular ,Chromosomes, Artificial, Yeast ,In Situ Hybridization, Fluorescence ,In vitro recombination ,Research Article ,Plasmids - Abstract
The feasibility of using the fission yeast, Schizosaccharomyces pombe , as a host for the propagation of cloned large fragments of human DNA has been investigated. Two acentric vector arms were utilized; these carry autonomously replicating sequences ( ars elements), selectable markers ( ura4(+) or LEU2 ) and 250 bp of S. pombe terminal telomeric repeats. All cloning was performed between the unique sites in both vector arms for the restriction endonuclease Not I. Initially the system was tested by converting six previously characterized cosmids from human chromosome 11p13 into a form that could be propagated in S.pombe as linear episomal elements of 50-60 kb in length. In all transformants analysed these cosmids were maintained intact. To test if larger fragments of human DNA could also be propagated total human DNA was digested with Not I and size fractionated by pulsed field gel electrophoresis (PFGE). Fractions of 100-1000 kb were ligated to Not I-digested vector arms and transformed into S.pombe protoplasts in the presence of lipofectin. Prototrophic ura+leu+transformants were obtained which upon examination by PFGE were found to contain additional linear chromosomes migrating at between 100 and 500 kb with a copy number of 5-10 copies/cell. Hybridization analyses revealed that these additional bands contained human DNA. Fluorescent in situ hybridization (FISH) analyses of several independent clones indicated that the inserts were derived from single loci within the human genome. These analyses clearly demonstrate that it is possible to clone large fragments of heterologous DNA in fission yeast using this S.p ombe artificial chromosome system which we have called SPARC. This vector-host system will complement the various other systems for cloning large DNA fragments.
- Published
- 1998
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