ALBERT

Beschreibung: A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1-0.0001%) form tumours when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, the extent to which NOD/SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg(-/-)) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597380/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597380/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quintana, Elsa -- Shackleton, Mark -- Sabel, Michael S -- Fullen, Douglas R -- Johnson, Timothy M -- Morrison, Sean J -- 5P60-DK20572/DK/NIDDK NIH HHS/ -- CA46592/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 4;456(7222):593-8. doi: 10.1038/nature07567.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052619" target="_blank"〉PubMed〈/a〉

Beschreibung: The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moore, Chris B -- Bergstralh, Daniel T -- Duncan, Joseph A -- Lei, Yu -- Morrison, Thomas E -- Zimmermann, Albert G -- Accavitti-Loper, Mary A -- Madden, Victoria J -- Sun, Lijun -- Ye, Zhengmao -- Lich, John D -- Heise, Mark T -- Chen, Zhijian -- Ting, Jenny P-Y -- England -- Nature. 2008 Jan 31;451(7178):573-7. doi: 10.1038/nature06501. Epub 2008 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18200010" target="_blank"〉PubMed〈/a〉

Beschreibung: Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P 〈 1 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joshi, Peter K -- Esko, Tonu -- Mattsson, Hannele -- Eklund, Niina -- Gandin, Ilaria -- Nutile, Teresa -- Jackson, Anne U -- Schurmann, Claudia -- Smith, Albert V -- Zhang, Weihua -- Okada, Yukinori -- Stancakova, Alena -- Faul, Jessica D -- Zhao, Wei -- Bartz, Traci M -- Concas, Maria Pina -- Franceschini, Nora -- Enroth, Stefan -- Vitart, Veronique -- Trompet, Stella -- Guo, Xiuqing -- Chasman, Daniel I -- O'Connel, Jeffrey R -- Corre, Tanguy -- Nongmaithem, Suraj S -- Chen, Yuning -- Mangino, Massimo -- Ruggiero, Daniela -- Traglia, Michela -- Farmaki, Aliki-Eleni -- Kacprowski, Tim -- Bjonnes, Andrew -- van der Spek, Ashley -- Wu, Ying -- Giri, Anil K -- Yanek, Lisa R -- Wang, Lihua -- Hofer, Edith -- Rietveld, Cornelius A -- McLeod, Olga -- Cornelis, Marilyn C -- Pattaro, Cristian -- Verweij, Niek -- Baumbach, Clemens -- Abdellaoui, Abdel -- Warren, Helen R -- Vuckovic, Dragana -- Mei, Hao -- Bouchard, Claude -- Perry, John R B -- Cappellani, Stefania -- Mirza, Saira S -- Benton, Miles C -- Broeckel, Ulrich -- Medland, Sarah E -- Lind, Penelope A -- Malerba, Giovanni -- Drong, Alexander -- Yengo, Loic -- Bielak, Lawrence F -- Zhi, Degui -- van der Most, Peter J -- Shriner, Daniel -- Magi, Reedik -- Hemani, Gibran -- Karaderi, Tugce -- Wang, Zhaoming -- Liu, Tian -- Demuth, Ilja -- Zhao, Jing Hua -- Meng, Weihua -- Lataniotis, Lazaros -- van der Laan, Sander W -- Bradfield, Jonathan P -- Wood, Andrew R -- Bonnefond, Amelie -- Ahluwalia, Tarunveer S -- Hall, Leanne M -- Salvi, Erika -- Yazar, Seyhan -- Carstensen, Lisbeth -- de Haan, Hugoline G -- Abney, Mark -- Afzal, Uzma -- Allison, Matthew A -- Amin, Najaf -- Asselbergs, Folkert W -- Bakker, Stephan J L -- Barr, R Graham -- Baumeister, Sebastian E -- Benjamin, Daniel J -- Bergmann, Sven -- Boerwinkle, Eric -- Bottinger, Erwin P -- Campbell, Archie -- Chakravarti, Aravinda -- Chan, Yingleong -- Chanock, Stephen J -- Chen, Constance -- Chen, Y-D Ida -- Collins, Francis S -- Connell, John -- Correa, Adolfo -- Cupples, L Adrienne -- Smith, George Davey -- Davies, Gail -- Dorr, Marcus -- Ehret, Georg -- Ellis, Stephen B -- Feenstra, Bjarke -- Feitosa, Mary F -- Ford, Ian -- Fox, Caroline S -- Frayling, Timothy M -- Friedrich, Nele -- Geller, Frank -- Scotland, Generation -- Gillham-Nasenya, Irina -- Gottesman, Omri -- Graff, Misa -- Grodstein, Francine -- Gu, Charles -- Haley, Chris -- Hammond, Christopher J -- Harris, Sarah E -- Harris, Tamara B -- Hastie, Nicholas D -- Heard-Costa, Nancy L -- Heikkila, Kauko -- Hocking, Lynne J -- Homuth, Georg -- Hottenga, Jouke-Jan -- Huang, Jinyan -- Huffman, Jennifer E -- Hysi, Pirro G -- Ikram, M Arfan -- Ingelsson, Erik -- Joensuu, Anni -- Johansson, Asa -- Jousilahti, Pekka -- Jukema, J Wouter -- Kahonen, Mika -- Kamatani, Yoichiro -- Kanoni, Stavroula -- Kerr, Shona M -- Khan, Nazir M -- Koellinger, Philipp -- Koistinen, Heikki A -- Kooner, Manraj K -- Kubo, Michiaki -- Kuusisto, Johanna -- Lahti, Jari -- Launer, Lenore J -- Lea, Rodney A -- Lehne, Benjamin -- Lehtimaki, Terho -- Liewald, David C M -- Lind, Lars -- Loh, Marie -- Lokki, Marja-Liisa -- London, Stephanie J -- Loomis, Stephanie J -- Loukola, Anu -- Lu, Yingchang -- Lumley, Thomas -- Lundqvist, Annamari -- Mannisto, Satu -- Marques-Vidal, Pedro -- Masciullo, Corrado -- Matchan, Angela -- Mathias, Rasika A -- Matsuda, Koichi -- Meigs, James B -- Meisinger, Christa -- Meitinger, Thomas -- Menni, Cristina -- Mentch, Frank D -- Mihailov, Evelin -- Milani, Lili -- Montasser, May E -- Montgomery, Grant W -- Morrison, Alanna -- Myers, Richard H -- Nadukuru, Rajiv -- Navarro, Pau -- Nelis, Mari -- Nieminen, Markku S -- Nolte, Ilja M -- O'Connor, George T -- Ogunniyi, Adesola -- Padmanabhan, Sandosh -- Palmas, Walter R -- Pankow, James S -- Patarcic, Inga -- Pavani, Francesca -- Peyser, Patricia A -- Pietilainen, Kirsi -- Poulter, Neil -- Prokopenko, Inga -- Ralhan, Sarju -- Redmond, Paul -- Rich, Stephen S -- Rissanen, Harri -- Robino, Antonietta -- Rose, Lynda M -- Rose, Richard -- Sala, Cinzia -- Salako, Babatunde -- Salomaa, Veikko -- Sarin, Antti-Pekka -- Saxena, Richa -- Schmidt, Helena -- Scott, Laura J -- Scott, William R -- Sennblad, Bengt -- Seshadri, Sudha -- Sever, Peter -- Shrestha, Smeeta -- Smith, Blair H -- Smith, Jennifer A -- Soranzo, Nicole -- Sotoodehnia, Nona -- Southam, Lorraine -- Stanton, Alice V -- Stathopoulou, Maria G -- Strauch, Konstantin -- Strawbridge, Rona J -- Suderman, Matthew J -- Tandon, Nikhil -- Tang, Sian-Tsun -- Taylor, Kent D -- Tayo, Bamidele O -- Toglhofer, Anna Maria -- Tomaszewski, Maciej -- Tsernikova, Natalia -- Tuomilehto, Jaakko -- Uitterlinden, Andre G -- Vaidya, Dhananjay -- van Hylckama Vlieg, Astrid -- van Setten, Jessica -- Vasankari, Tuula -- Vedantam, Sailaja -- Vlachopoulou, Efthymia -- Vozzi, Diego -- Vuoksimaa, Eero -- Waldenberger, Melanie -- Ware, Erin B -- Wentworth-Shields, William -- Whitfield, John B -- Wild, Sarah -- Willemsen, Gonneke -- Yajnik, Chittaranjan S -- Yao, Jie -- Zaza, Gianluigi -- Zhu, Xiaofeng -- BioBank Japan Project -- Salem, Rany M -- Melbye, Mads -- Bisgaard, Hans -- Samani, Nilesh J -- Cusi, Daniele -- Mackey, David A -- Cooper, Richard S -- Froguel, Philippe -- Pasterkamp, Gerard -- Grant, Struan F A -- Hakonarson, Hakon -- Ferrucci, Luigi -- Scott, Robert A -- Morris, Andrew D -- Palmer, Colin N A -- Dedoussis, George -- Deloukas, Panos -- Bertram, Lars -- Lindenberger, Ulman -- Berndt, Sonja I -- Lindgren, Cecilia M -- Timpson, Nicholas J -- Tonjes, Anke -- Munroe, Patricia B -- Sorensen, Thorkild I A -- Rotimi, Charles N -- Arnett, Donna K -- Oldehinkel, Albertine J -- Kardia, Sharon L R -- Balkau, Beverley -- Gambaro, Giovanni -- Morris, Andrew P -- Eriksson, Johan G -- Wright, Margie J -- Martin, Nicholas G -- Hunt, Steven C -- Starr, John M -- Deary, Ian J -- Griffiths, Lyn R -- Tiemeier, Henning -- Pirastu, Nicola -- Kaprio, Jaakko -- Wareham, Nicholas J -- Perusse, Louis -- Wilson, James G -- Girotto, Giorgia -- Caulfield, Mark J -- Raitakari, Olli -- Boomsma, Dorret I -- Gieger, Christian -- van der Harst, Pim -- Hicks, Andrew A -- Kraft, Peter -- Sinisalo, Juha -- Knekt, Paul -- Johannesson, Magnus -- Magnusson, Patrik K E -- Hamsten, Anders -- Schmidt, Reinhold -- Borecki, Ingrid B -- Vartiainen, Erkki -- Becker, Diane M -- Bharadwaj, Dwaipayan -- Mohlke, Karen L -- Boehnke, Michael -- van Duijn, Cornelia M -- Sanghera, Dharambir K -- Teumer, Alexander -- Zeggini, Eleftheria -- Metspalu, Andres -- Gasparini, Paolo -- Ulivi, Sheila -- Ober, Carole -- Toniolo, Daniela -- Rudan, Igor -- Porteous, David J -- Ciullo, Marina -- Spector, Tim D -- Hayward, Caroline -- Dupuis, Josee -- Loos, Ruth J F -- Wright, Alan F -- Chandak, Giriraj R -- Vollenweider, Peter -- Shuldiner, Alan R -- Ridker, Paul M -- Rotter, Jerome I -- Sattar, Naveed -- Gyllensten, Ulf -- North, Kari E -- Pirastu, Mario -- Psaty, Bruce M -- Weir, David R -- Laakso, Markku -- Gudnason, Vilmundur -- Takahashi, Atsushi -- Chambers, John C -- Kooner, Jaspal S -- Strachan, David P -- Campbell, Harry -- Hirschhorn, Joel N -- Perola, Markus -- Polasek, Ozren -- Wilson, James F -- 068545/Wellcome Trust/United Kingdom -- 072856/Wellcome Trust/United Kingdom -- 072960/Wellcome Trust/United Kingdom -- 079771/Wellcome Trust/United Kingdom -- 084723/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 099194/Wellcome Trust/United Kingdom -- 105022/Wellcome Trust/United Kingdom -- 250157/European Research Council/International -- 280559/European Research Council/International -- 323195/European Research Council/International -- BARCVBRU-2012-1/Department of Health/United Kingdom -- BB/F019394/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- CZB/4/276/Chief Scientist Office/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- CZD/16/6/Chief Scientist Office/United Kingdom -- CZD/16/6/2/Chief Scientist Office/United Kingdom -- CZD/16/6/3/Chief Scientist Office/United Kingdom -- CZD/16/6/4/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- MC_UU_12013/3/Medical Research Council/United Kingdom -- MC_UU_12015/1/Medical Research Council/United Kingdom -- MR/K026992/1/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- P30 DK020572/DK/NIDDK NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R03 DC013373/DC/NIDCD NIH HHS/ -- RG/2001004/12869/British Heart Foundation/United Kingdom -- RP-PG-0407-10371/Department of Health/United Kingdom -- SAG09977/Biotechnology and Biological Sciences Research Council/United Kingdom -- UL1 TR000124/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Jul 23;523(7561):459-62. doi: 10.1038/nature14618. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [4] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; 1] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. ; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. ; Institute of Genetics and Biophysics "A. Buzzati-Traverso" CNR, via Pietro Castellino, 111, 80131 Naples, Italy. ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Icelandic Heart Association, Holtasmari 1, 201, Kopavogur, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland. ; Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, Michigan 48104, USA. ; Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. ; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; Institute of Population Genetics, National Research Council, Trav. La Crucca n. 3 - Reg. Baldinca, 07100 Sassari, Italy. ; Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. ; Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; 1] Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. [2] Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, East, Harvard Medical School, Boston, Boston, Massachusetts 02215, USA. ; Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. ; 1] Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland. [2] Swiss Institute of Bioinformatics, Quartier Sorge - batiment genopode, Lausanne, 1015, Switzerland. ; Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. ; Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. ; 1] Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. [2] NIHR Biomedical Research Centre, Guy's and St. Thomas' Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy. ; Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens 17671, Greece. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, Greifswald 17475, Germany. ; Center for Human Genetic Research, 55 Fruit Street, Massachusetts General Hospital, Massachusetts 02114, USA. ; Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. ; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Department of Genetics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. [2] Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz2, Graz, A-8036, Austria. ; Erasmus School of Economics, Erasmus University Rotterdam, Burgemeester Oudlaan 50, Rotterdam, 3000 DR, The Netherlands. ; Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. ; 1] Channing Division of Network Medicine, Brigham &Women's Hospital, 181 Longwood, Boston, Massachusetts 02115, USA. [2] Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), 39100 Bolzano, Italy (affiliated Institute of the University of Lubeck, D-23562 Lubeck, Germany). ; University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [3] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Amsterdam, 1081 BT, The Netherlands. ; 1] Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. [2] NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ; Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, Mississippi 39216, USA. ; Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, Louisiana 70808, USA. ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, GPO Box 2434, Brisbane Queensland 4001, Australia. ; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, Wisconsin 53226, USA. ; Quantitative Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane Queensland 4006, Australia. ; Dipartimento di Scienze della Vita e della Riproduzione, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. ; Department of Biostatistics, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, Alabama 35294, USA. ; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, P.O. box 30.001, 9700 RB, Groningen, The Netherlands. ; Center for Research on Genomics and Global Health, National Human Genome Research Institute, Building 12A/Room 4047, 12 South Dr., Bethesda, Maryland 20892, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. ; MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. ; 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. [2] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. ; 1] Charite Research Group on Geriatrics, Charite - Universitatsmedizin Berlin, Reinickendorferstr. 61, 13347 Berlin, Germany. [2] Institute of Medical and Human Genetics, Charite - Universitatsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany. ; Division of Population Health Sciences, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD2 4BF, UK. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. ; Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. ; Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. ; 1] COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Steno Diabetes Centre, Niels Steensens Vej 2, Gentofte, 2820, Denmark. ; Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; Department of Health Sciences, University of Milan, via A. di Rudini 8, 20142 Milan, Italy. ; Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, 2 Verdun Street, Perth, Western Australia 6009, Australia. ; Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. ; Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, Illinois 60637, USA. ; Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; 1] Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, Gower Street, London WC1E 6BT, UK. ; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Medicine, Columbia University, 622 W. 168th Street, New York, New York 10032, USA. ; Institute for Community Medicine, University Medicine Greifswald, W.-Rathenau-Str. 48, Greifswald 17475, Germany. ; 1] Department of Economics, Cornell University, 480 Uris Hall, Ithaca, New York 14853, USA. [2] Department of Economics and Center for Economic and Social Research, University of Southern California, 314C Dauterive Hall, 635 Downey Way, Los Angeles, California 90089, USA. ; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Suite 453E, Houston, Texas 77030, USA. ; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [3] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. ; Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, Massachusetts 02115, USA. ; Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, College Office, Level 10, Dundee DD1 9SY, UK. ; 1] Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. [2] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. ; 1] Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald 17475, Germany. ; 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Geneve 14, 1211, Switzerland. ; Robertson Centre, University of Glasgow, Boyd Orr Building, Glasgow G12 8QQ, Scotland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, Massachusetts 02115, USA. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, 17475 Greifswald, Germany. ; Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. ; Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Division of Biostatistics, Washington University, 660 S Euclid, St Louis, Missouri 63110, USA. ; 1] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. [2] Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK. ; 1] Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; National Institutes on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Department of Neurology, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. ; Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. ; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Radiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SE-17121, Sweden. ; 1] Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. [2] Uppsala Clinical Research Center, Uppsala University, Uppsala, SE-75237, Sweden. ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Cardiology C5-P, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Clinical Physiology, University of Tampere and Tampere University Hospital, P.O. Box 2000, Tampere, FI-33521, Finland. ; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki, FI-00290, Finland. ; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; Laboratory for Genotyping Development RCfIMS, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, FI-70210, Finland. ; 1] Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, University of Helsinki, Helsinki, FI-00014, Finland. [2] Folkhalsan Reasearch Centre, PB 63, Helsinki, FI-00014 University of Helsinki, Finland. ; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. ; Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, FI-33520, Finland. ; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Medical Sciences, University Hospital, Uppsala, 75185, Sweden. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, 138648, Singapore. ; Transplantation laboratory, Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki, FI-00014, Finland. ; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA. ; Ophthalmology, Massachusetts Eye and Ear, 243 Charles Street, Boston, Massachusetts 02114, USA. ; Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, 1142, New Zealand. ; Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Internal Medicine, University Hospital, Rue du Bugnon 44, Lausanne, 1011, Switzerland. ; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. ; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. ; Division of General Internal Medicine, Massachusetts General Hospital, 50 Staniford St, Boston, Massachusetts 02114, USA. ; Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Human Genetics, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Str. 22, Munchen 81675, Germany. ; Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, Massachusetts 02118, USA. ; HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FI-00029, Finland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Pulmonary Center and Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Medicine, University of Ibadan, Ibadan, Nigeria. ; ICAMS, University of Glasgow, 126 University Way, Glasgow G12 8TA, UK. ; Division of Epidemiology and Community Health, University of Minnesota, 1300 S 2nd Street, Minneapolis, Minnesota 55454, USA. ; Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, FI-00014, Helsinki, Finland. ; International Centre for Circulatory Health, Imperial College London, London W2 1LA, UK. ; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; Department of Cardiology and Cardio thoracic Surgery Hero DMC Heart Institute, Civil Lines, 141001, Ludhiana, India. ; Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department Public Health Sciences, University of Virginia School of Medicine, 3232 West Complex, Charlottesville, Virginia 22908, USA. ; Department of Psychological &Brain Sciences, Indiana University Bloomington, 1101 E. 10th Street, Bloomington, Indiana 47405, USA. ; Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, A-8010, Austria. ; 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. [2] Science for Life Laboratory, Karolinska Institutet, Stockholm, SE-17121, Sweden. ; University of Dundee, Kirsty Semple Way, Dundee DD2 4DB, UK. ; Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. ; UMR INSERM U1122; IGE-PCV "Interactions Gene-Environnement en Physiopathologie Cardio-Vasculaire", INSERM, University of Lorraine, 30 Rue Lionnois, 54000 Nancy, France. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, Munich 81377, Germany. ; Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, 110029, India. ; National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. ; Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA. ; 1] Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. [2] NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, 51010, Estonia. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, FI-00250, Finland. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Centre for Population Health Sciences, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, 411011, India. ; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. ; Renal Unit, Department of Medicine, University of Verona, Piazzale A. Stefani 1, 37124 Verona, Italy. ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA. ; 1] Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. [2] Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. ; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. ; 1] CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. [2] Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; 1] Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. [2] Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Translational Gerontology Branch, National institute on Aging, Baltimore, Maryland 21225, USA. ; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, No. 9 Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, UK. ; Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD1 9SY, UK. ; 1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK [2] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia. ; 1] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. [2] Faculty of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London W6 8RP, UK. [3] Institutes for Neurogenetics and Integrative &Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. ; Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; Department of Medicine, University of Leipzig, Leipzig 04103, Germany. ; 1] MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, 2000, Denmark. ; Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294, USA. ; Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen, 9700 RB, The Netherlands. ; Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif, France. ; Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, 00168 Roma, Italy. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [3] Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool L69 3GA, UK. ; 1] Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, University of Helsinki, Helsinki, FI-00014, Finland. [3] Vasa Central Hospital, Sandviksgatan 2-4, Vasa, FI-65130, Finland. [4] Folkhalsan Reasearch Centre, PB 63, University of Helsinki, Helsinki, FI-00014, Finland. [5] Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, FI-00290, Finland. ; Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Room 1160, Salt Lake City, Utah 84117, USA. ; 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. [2] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. [3] National Institute for Health and Welfare (THL), P.O.Box 30, Mannerheimintie 166, Helsinki, FI-00271, Finland. ; Department of Kinesiology, Laval University, 2300 rue de la Terrasse, Quebec G1V 0A6, Canada. ; Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, Mississippi 39216, USA. ; 1] Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, FI-20521, Finland. [2] Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, FI-20521, Finland. ; 1] University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, SE-113 83, Sweden. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-171 77, Sweden. ; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. ; Department of Genetics and Biostatistics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; 1] Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. [2] School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. ; 1] Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, Oklahoma 73104, USA. [2] Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. ; 1] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. [2] Sidra Medical and Research Centre, Doha, Qatar. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [3] The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. [2] Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore. ; 1] Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [2] Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [3] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, Maryland 21201, USA. ; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. ; 1] Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin Street, Suite 306, Chapel Hill, North Carolina 27599, USA. ; 1] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. [2] Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; 1] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; Population Health Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131930" target="_blank"〉PubMed〈/a〉

Beschreibung: Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759979/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Richard Mark -- Cech, Jennifer -- Ratanasirintrawoot, Sutheera -- Lin, Charles Y -- Rahl, Peter B -- Burke, Christopher J -- Langdon, Erin -- Tomlinson, Matthew L -- Mosher, Jack -- Kaufman, Charles -- Chen, Frank -- Long, Hannah K -- Kramer, Martin -- Datta, Sumon -- Neuberg, Donna -- Granter, Scott -- Young, Richard A -- Morrison, Sean -- Wheeler, Grant N -- Zon, Leonard I -- K08 AR055368/AR/NIAMS NIH HHS/ -- R01 CA103846/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG002668-08/HG/NHGRI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 24;471(7339):518-22. doi: 10.1038/nature09882.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430780" target="_blank"〉PubMed〈/a〉

Beschreibung: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (〉/=140 mm Hg systolic blood pressure or 〉/=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340926/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340926/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉International Consortium for Blood Pressure Genome-Wide Association Studies -- Ehret, Georg B -- Munroe, Patricia B -- Rice, Kenneth M -- Bochud, Murielle -- Johnson, Andrew D -- Chasman, Daniel I -- Smith, Albert V -- Tobin, Martin D -- Verwoert, Germaine C -- Hwang, Shih-Jen -- Pihur, Vasyl -- Vollenweider, Peter -- O'Reilly, Paul F -- Amin, Najaf -- Bragg-Gresham, Jennifer L -- Teumer, Alexander -- Glazer, Nicole L -- Launer, Lenore -- Zhao, Jing Hua -- Aulchenko, Yurii -- Heath, Simon -- Sober, Siim -- Parsa, Afshin -- Luan, Jian'an -- Arora, Pankaj -- Dehghan, Abbas -- Zhang, Feng -- Lucas, Gavin -- Hicks, Andrew A -- Jackson, Anne U -- Peden, John F -- Tanaka, Toshiko -- Wild, Sarah H -- Rudan, Igor -- Igl, Wilmar -- Milaneschi, Yuri -- Parker, Alex N -- Fava, Cristiano -- Chambers, John C -- Fox, Ervin R -- Kumari, Meena -- Go, Min Jin -- van der Harst, Pim -- Kao, Wen Hong Linda -- Sjogren, Marketa -- Vinay, D G -- Alexander, Myriam -- Tabara, Yasuharu -- Shaw-Hawkins, Sue -- Whincup, Peter H -- Liu, Yongmei -- Shi, Gang -- Kuusisto, Johanna -- Tayo, Bamidele -- Seielstad, Mark -- Sim, Xueling -- Nguyen, Khanh-Dung Hoang -- Lehtimaki, Terho -- Matullo, Giuseppe -- Wu, Ying -- Gaunt, Tom R -- Onland-Moret, N Charlotte -- Cooper, Matthew N -- Platou, Carl G P -- Org, Elin -- Hardy, Rebecca -- Dahgam, Santosh -- Palmen, Jutta -- Vitart, Veronique -- Braund, Peter S -- Kuznetsova, Tatiana -- Uiterwaal, Cuno S P M -- Adeyemo, Adebowale -- Palmas, Walter -- Campbell, Harry -- Ludwig, Barbara -- Tomaszewski, Maciej -- Tzoulaki, Ioanna -- Palmer, Nicholette D -- CARDIoGRAM consortium -- CKDGen Consortium -- KidneyGen Consortium -- EchoGen consortium -- CHARGE-HF consortium -- Aspelund, Thor -- Garcia, Melissa -- Chang, Yen-Pei C -- O'Connell, Jeffrey R -- Steinle, Nanette I -- Grobbee, Diederick E -- Arking, Dan E -- Kardia, Sharon L -- Morrison, Alanna C -- Hernandez, Dena -- Najjar, Samer -- McArdle, Wendy L -- Hadley, David -- Brown, Morris J -- Connell, John M -- Hingorani, Aroon D -- Day, Ian N M -- Lawlor, Debbie A -- Beilby, John P -- Lawrence, Robert W -- Clarke, Robert -- Hopewell, Jemma C -- Ongen, Halit -- Dreisbach, Albert W -- Li, Yali -- Young, J Hunter -- Bis, Joshua C -- Kahonen, Mika -- Viikari, Jorma -- Adair, Linda S -- Lee, Nanette R -- Chen, Ming-Huei -- Olden, Matthias -- Pattaro, Cristian -- Bolton, Judith A Hoffman -- Kottgen, Anna -- Bergmann, Sven -- Mooser, Vincent -- Chaturvedi, Nish -- Frayling, Timothy M -- Islam, Muhammad -- Jafar, Tazeen H -- Erdmann, Jeanette -- Kulkarni, Smita R -- Bornstein, Stefan R -- Grassler, Jurgen -- Groop, Leif -- Voight, Benjamin F -- Kettunen, Johannes -- Howard, Philip -- Taylor, Andrew -- Guarrera, Simonetta -- Ricceri, Fulvio -- Emilsson, Valur -- Plump, Andrew -- Barroso, Ines -- Khaw, Kay-Tee -- Weder, Alan B -- Hunt, Steven C -- Sun, Yan V -- Bergman, Richard N -- Collins, Francis S -- Bonnycastle, Lori L -- Scott, Laura J -- Stringham, Heather M -- Peltonen, Leena -- Perola, Markus -- Vartiainen, Erkki -- Brand, Stefan-Martin -- Staessen, Jan A -- Wang, Thomas J -- Burton, Paul R -- Soler Artigas, Maria -- Dong, Yanbin -- Snieder, Harold -- Wang, Xiaoling -- Zhu, Haidong -- Lohman, Kurt K -- Rudock, Megan E -- Heckbert, Susan R -- Smith, Nicholas L -- Wiggins, Kerri L -- Doumatey, Ayo -- Shriner, Daniel -- Veldre, Gudrun -- Viigimaa, Margus -- Kinra, Sanjay -- Prabhakaran, Dorairaj -- Tripathy, Vikal -- Langefeld, Carl D -- Rosengren, Annika -- Thelle, Dag S -- Corsi, Anna Maria -- Singleton, Andrew -- Forrester, Terrence -- Hilton, Gina -- McKenzie, Colin A -- Salako, Tunde -- Iwai, Naoharu -- Kita, Yoshikuni -- Ogihara, Toshio -- Ohkubo, Takayoshi -- Okamura, Tomonori -- Ueshima, Hirotsugu -- Umemura, Satoshi -- Eyheramendy, Susana -- Meitinger, Thomas -- Wichmann, H-Erich -- Cho, Yoon Shin -- Kim, Hyung-Lae -- Lee, Jong-Young -- Scott, James -- Sehmi, Joban S -- Zhang, Weihua -- Hedblad, Bo -- Nilsson, Peter -- Smith, George Davey -- Wong, Andrew -- Narisu, Narisu -- Stancakova, Alena -- Raffel, Leslie J -- Yao, Jie -- Kathiresan, Sekar -- O'Donnell, Christopher J -- Schwartz, Stephen M -- Ikram, M Arfan -- Longstreth, W T Jr -- Mosley, Thomas H -- Seshadri, Sudha -- Shrine, Nick R G -- Wain, Louise V -- Morken, Mario A -- Swift, Amy J -- Laitinen, Jaana -- Prokopenko, Inga -- Zitting, Paavo -- Cooper, Jackie A -- Humphries, Steve E -- Danesh, John -- Rasheed, Asif -- Goel, Anuj -- Hamsten, Anders -- Watkins, Hugh -- Bakker, Stephan J L -- van Gilst, Wiek H -- Janipalli, Charles S -- Mani, K Radha -- Yajnik, Chittaranjan S -- Hofman, Albert -- Mattace-Raso, Francesco U S -- Oostra, Ben A -- Demirkan, Ayse -- Isaacs, Aaron -- Rivadeneira, Fernando -- Lakatta, Edward G -- Orru, Marco -- Scuteri, Angelo -- Ala-Korpela, Mika -- Kangas, Antti J -- Lyytikainen, Leo-Pekka -- Soininen, Pasi -- Tukiainen, Taru -- Wurtz, Peter -- Ong, Rick Twee-Hee -- Dorr, Marcus -- Kroemer, Heyo K -- Volker, Uwe -- Volzke, Henry -- Galan, Pilar -- Hercberg, Serge -- Lathrop, Mark -- Zelenika, Diana -- Deloukas, Panos -- Mangino, Massimo -- Spector, Tim D -- Zhai, Guangju -- Meschia, James F -- Nalls, Michael A -- Sharma, Pankaj -- Terzic, Janos -- Kumar, M V Kranthi -- Denniff, Matthew -- Zukowska-Szczechowska, Ewa -- Wagenknecht, Lynne E -- Fowkes, F Gerald R -- Charchar, Fadi J -- Schwarz, Peter E H -- Hayward, Caroline -- Guo, Xiuqing -- Rotimi, Charles -- Bots, Michiel L -- Brand, Eva -- Samani, Nilesh J -- Polasek, Ozren -- Talmud, Philippa J -- Nyberg, Fredrik -- Kuh, Diana -- Laan, Maris -- Hveem, Kristian -- Palmer, Lyle J -- van der Schouw, Yvonne T -- Casas, Juan P -- Mohlke, Karen L -- Vineis, Paolo -- Raitakari, Olli -- Ganesh, Santhi K -- Wong, Tien Y -- Tai, E Shyong -- Cooper, Richard S -- Laakso, Markku -- Rao, Dabeeru C -- Harris, Tamara B -- Morris, Richard W -- Dominiczak, Anna F -- Kivimaki, Mika -- Marmot, Michael G -- Miki, Tetsuro -- Saleheen, Danish -- Chandak, Giriraj R -- Coresh, Josef -- Navis, Gerjan -- Salomaa, Veikko -- Han, Bok-Ghee -- Zhu, Xiaofeng -- Kooner, Jaspal S -- Melander, Olle -- Ridker, Paul M -- Bandinelli, Stefania -- Gyllensten, Ulf B -- Wright, Alan F -- Wilson, James F -- Ferrucci, Luigi -- Farrall, Martin -- Tuomilehto, Jaakko -- Pramstaller, Peter P -- Elosua, Roberto -- Soranzo, Nicole -- Sijbrands, Eric J G -- Altshuler, David -- Loos, Ruth J F -- Shuldiner, Alan R -- Gieger, Christian -- Meneton, Pierre -- Uitterlinden, Andre G -- Wareham, Nicholas J -- Gudnason, Vilmundur -- Rotter, Jerome I -- Rettig, Rainer -- Uda, Manuela -- Strachan, David P -- Witteman, Jacqueline C M -- Hartikainen, Anna-Liisa -- Beckmann, Jacques S -- Boerwinkle, Eric -- Vasan, Ramachandran S -- Boehnke, Michael -- Larson, Martin G -- Jarvelin, Marjo-Riitta -- Psaty, Bruce M -- Abecasis, Goncalo R -- Chakravarti, Aravinda -- Elliott, Paul -- van Duijn, Cornelia M -- Newton-Cheh, Christopher -- Levy, Daniel -- Caulfield, Mark J -- Johnson, Toby -- 068545/Z/02/Wellcome Trust/United Kingdom -- 070191/Z/03/Z/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 080747/Z/06/Z/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 1R01AG032098-01A/AG/NIA NIH HHS/ -- 1RL1MH083268-01/MH/NIMH NIH HHS/ -- 263 MD 821336/MD/NIMHD NIH HHS/ -- 263 MD 9164/MD/NIMHD NIH HHS/ -- 263-MA-410953/PHS HHS/ -- 2M01RR010284/RR/NCRR NIH HHS/ -- 33014/PHS HHS/ -- 55005617/Howard Hughes Medical Institute/ -- 5R01HL086694-03/HL/NHLBI NIH HHS/ -- 5R01HL087679-02/HL/NHLBI NIH HHS/ -- 5R01HL08770002/HL/NHLBI NIH HHS/ -- 5R01MH63706:02/MH/NIMH NIH HHS/ -- 5U01CA086308/CA/NCI NIH HHS/ -- AG13196/AG/NIA NIH HHS/ -- CH/03/001/British Heart Foundation/United Kingdom -- CZB/4/276/Chief Scientist Office/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- DK062370/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK072193/DK/NIDDK NIH HHS/ -- DK075787/DK/NIDDK NIH HHS/ -- DK078150/DK/NIDDK NIH HHS/ -- DK56350/DK/NIDDK NIH HHS/ -- ES10126/ES/NIEHS NIH HHS/ -- FS05/125/British Heart Foundation/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0100222/Medical Research Council/United Kingdom -- G0400874/Medical Research Council/United Kingdom -- G0401527/Medical Research Council/United Kingdom -- G0500539/Medical Research Council/United Kingdom -- G0501942/British Heart Foundation/United Kingdom -- G0501942/Medical Research Council/United Kingdom -- G0600331/Medical Research Council/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G0902037/Medical Research Council/United Kingdom -- G0902313/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- G19/35/Medical Research Council/United Kingdom -- G20234/Biotechnology and Biological Sciences Research Council/United Kingdom -- G8802774/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9521010D/Medical Research Council/United Kingdom -- HG003054/HG/NHGRI NIH HHS/ -- HG005581/HG/NHGRI NIH HHS/ -- HHSN268200625226C/PHS HHS/ -- HHSN268200782096/PHS HHS/ -- HHSN268200782096C/PHS HHS/ -- HL 54512/HL/NHLBI NIH HHS/ -- HL-87660/HL/NHLBI NIH HHS/ -- HL043851/HL/NHLBI NIH HHS/ -- HL080025/HL/NHLBI NIH HHS/ -- HL084729/HL/NHLBI NIH HHS/ -- HL085144/HL/NHLBI NIH HHS/ -- HL086718/HL/NHLBI NIH HHS/ -- HL087647/HL/NHLBI NIH HHS/ -- HL098283/HL/NHLBI NIH HHS/ -- HL36310/HL/NHLBI NIH HHS/ -- HL45508/HL/NHLBI NIH HHS/ -- HL53353/HL/NHLBI NIH HHS/ -- HL54512/HL/NHLBI NIH HHS/ -- HS06516/HS/AHRQ HHS/ -- K12RR023250/RR/NCRR NIH HHS/ -- M01 RR16500/RR/NCRR NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- MC_U123092720/Medical Research Council/United Kingdom -- MC_U123092723/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- MC_U137686857/Medical Research Council/United Kingdom -- MC_UP_A100_1003/Medical Research Council/United Kingdom -- MOP-82810/Canadian Institutes of Health Research/Canada -- MOP172605/Canadian Institutes of Health Research/Canada -- MOP77682/Canadian Institutes of Health Research/Canada -- N01 HC-15103/HC/NHLBI NIH HHS/ -- N01 HC-55222/HC/NHLBI NIH HHS/ -- N01 HC-95159/HC/NHLBI NIH HHS/ -- N01 HC-95169/HC/NHLBI NIH HHS/ -- N01-AG-1-2109/AG/NIA NIH HHS/ -- N01-AG-12100/AG/NIA NIH HHS/ -- N01-HC-25195/HC/NHLBI NIH HHS/ -- N01-HC-35129/HC/NHLBI NIH HHS/ -- N01-HC-45133/HC/NHLBI NIH HHS/ -- N01-HC-55015/HC/NHLBI NIH HHS/ -- N01-HC-55016/HC/NHLBI NIH HHS/ -- N01-HC-55018/HC/NHLBI NIH HHS/ -- N01-HC-55019/HC/NHLBI NIH HHS/ -- N01-HC-55020/HC/NHLBI NIH HHS/ -- N01-HC-55021/HC/NHLBI NIH HHS/ -- N01-HC-55022/HC/NHLBI NIH HHS/ -- N01-HC-75150/HC/NHLBI NIH HHS/ -- N01-HC-85079/HC/NHLBI NIH HHS/ -- N01-HC-85080/HC/NHLBI NIH HHS/ -- N01-HC-85081/HC/NHLBI NIH HHS/ -- N01-HC-85082/HC/NHLBI NIH HHS/ -- N01-HC-85083/HC/NHLBI NIH HHS/ -- N01-HC-85084/HC/NHLBI NIH HHS/ -- N01-HC-85085/HC/NHLBI NIH HHS/ -- N01-HC-85086/HC/NHLBI NIH HHS/ -- N01-HC-95160/HC/NHLBI NIH HHS/ -- 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Foundation/United Kingdom -- RG/08/008/25291/British Heart Foundation/United Kingdom -- RG/08/013/25942/British Heart Foundation/United Kingdom -- RG/08/014/24067/British Heart Foundation/United Kingdom -- RG/98002/British Heart Foundation/United Kingdom -- RG08/01/British Heart Foundation/United Kingdom -- RR-024156/RR/NCRR NIH HHS/ -- RR20649/RR/NCRR NIH HHS/ -- S06GM008016-320107/GM/NIGMS NIH HHS/ -- S06GM008016-380111/GM/NIGMS NIH HHS/ -- SP/04/002/British Heart Foundation/United Kingdom -- SP/08/005/25115/British Heart Foundation/United Kingdom -- TW008288/TW/FIC NIH HHS/ -- TW05596/TW/FIC NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 GM074518-04/GM/NIGMS NIH HHS/ -- U01 HL054466/HL/NHLBI NIH HHS/ -- U01 HL054466-11/HL/NHLBI NIH HHS/ -- U01 HL054471/HL/NHLBI NIH HHS/ -- U01 HL054473/HL/NHLBI NIH HHS/ -- U01 HL054527/HL/NHLBI NIH HHS/ -- U01 HL072515-06/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U01 NS069208/NS/NINDS NIH HHS/ -- U01 NS069208-01/NS/NINDS NIH HHS/ -- U01DE018903/DE/NIDCR NIH HHS/ -- U01DE01899/DE/NIDCR NIH HHS/ -- U01HG004399/HG/NHGRI NIH HHS/ -- U01HG004402/HG/NHGRI NIH HHS/ -- U01HG004415/HG/NHGRI NIH HHS/ -- U01HG004422/HG/NHGRI NIH HHS/ -- U01HG004423/HG/NHGRI NIH HHS/ -- U01HG004436/HG/NHGRI NIH HHS/ -- U01HG004438/HG/NHGRI NIH HHS/ -- U01HG004446/HG/NHGRI NIH HHS/ -- U01HG004726/HG/NHGRI NIH HHS/ -- U01HG004728/HG/NHGRI NIH HHS/ -- U01HG004729/HG/NHGRI NIH HHS/ -- U01HG004735/HG/NHGRI NIH HHS/ -- U01HG004738/HG/NHGRI NIH HHS/ -- U10 HL054512/HL/NHLBI NIH HHS/ -- U10HL054512/HL/NHLBI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1RR025005/RR/NCRR NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 11;478(7367):103-9. doi: 10.1038/nature10405.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909115" target="_blank"〉PubMed〈/a〉

Beschreibung: Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Some cancers also contain a hierarchy in which tumorigenic cancer stem cells differentiate into non-tumorigenic progeny. However, it remains unclear what fraction of cancers follow the stem-cell model and what clinical behaviours the model explains. Studies using lineage tracing and deep sequencing could have implications for the cancer stem-cell model and may help to determine the extent to which it accounts for therapy resistance and disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521623/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meacham, Corbin E -- Morrison, Sean J -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 19;501(7467):328-37. doi: 10.1038/nature12624.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24048065" target="_blank"〉PubMed〈/a〉

Beschreibung: Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 x 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 x 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 x 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ruark, Elise -- Snape, Katie -- Humburg, Peter -- Loveday, Chey -- Bajrami, Ilirjana -- Brough, Rachel -- Rodrigues, Daniel Nava -- Renwick, Anthony -- Seal, Sheila -- Ramsay, Emma -- Duarte, Silvana Del Vecchio -- Rivas, Manuel A -- Warren-Perry, Margaret -- Zachariou, Anna -- Campion-Flora, Adriana -- Hanks, Sandra -- Murray, Anne -- Ansari Pour, Naser -- Douglas, Jenny -- Gregory, Lorna -- Rimmer, Andrew -- Walker, Neil M -- Yang, Tsun-Po -- Adlard, Julian W -- Barwell, Julian -- Berg, Jonathan -- Brady, Angela F -- Brewer, Carole -- Brice, Glen -- Chapman, Cyril -- Cook, Jackie -- Davidson, Rosemarie -- Donaldson, Alan -- Douglas, Fiona -- Eccles, Diana -- Evans, D Gareth -- Greenhalgh, Lynn -- Henderson, Alex -- Izatt, Louise -- Kumar, Ajith -- Lalloo, Fiona -- Miedzybrodzka, Zosia -- Morrison, Patrick J -- Paterson, Joan -- Porteous, Mary -- Rogers, Mark T -- Shanley, Susan -- Walker, Lisa -- Gore, Martin -- Houlston, Richard -- Brown, Matthew A -- Caufield, Mark J -- Deloukas, Panagiotis -- McCarthy, Mark I -- Todd, John A -- Breast and Ovarian Cancer Susceptibility Collaboration -- Wellcome Trust Case Control Consortium -- Turnbull, Clare -- Reis-Filho, Jorge S -- Ashworth, Alan -- Antoniou, Antonis C -- Lord, Christopher J -- Donnelly, Peter -- Rahman, Nazneen -- 068545/Z/02/Wellcome Trust/United Kingdom -- 083948/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 091157/Wellcome Trust/United Kingdom -- 095552/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- 11174/Cancer Research UK/United Kingdom -- C12292/A11174/Cancer Research UK/United Kingdom -- CZB/4/540/Chief Scientist Office/United Kingdom -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G0900747 91070/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- England -- Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics & Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242139" target="_blank"〉PubMed〈/a〉

Beschreibung: Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514480/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morrison, Sean J -- Scadden, David T -- EB014703/EB/NIBIB NIH HHS/ -- HL044851/HL/NHLBI NIH HHS/ -- HL096372/HL/NHLBI NIH HHS/ -- HL097760/HL/NHLBI NIH HHS/ -- R01 EB014703/EB/NIBIB NIH HHS/ -- R01 HL044851/HL/NHLBI NIH HHS/ -- R01 HL097760/HL/NHLBI NIH HHS/ -- R03 HL096372/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 16;505(7483):327-34. doi: 10.1038/nature12984.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Stem Cell Institute and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24429631" target="_blank"〉PubMed〈/a〉

Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morello, Lauren -- Morrison, Jessica -- Reardon, Sara -- Tollefson, Jeff -- Witze, Alexandra -- England -- Nature. 2014 Mar 13;507(7491):147-8. doi: 10.1038/507147a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24622181" target="_blank"〉PubMed〈/a〉

Beschreibung: Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408792/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408792/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Youngjin -- Morrison, Brett M -- Li, Yun -- Lengacher, Sylvain -- Farah, Mohamed H -- Hoffman, Paul N -- Liu, Yiting -- Tsingalia, Akivaga -- Jin, Lin -- Zhang, Ping-Wu -- Pellerin, Luc -- Magistretti, Pierre J -- Rothstein, Jeffrey D -- NS33958/NS/NINDS NIH HHS/ -- P01NS16375/NS/NINDS NIH HHS/ -- P50AG05146/AG/NIA NIH HHS/ -- R01 NS033958/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Jul 26;487(7408):443-8. doi: 10.1038/nature11314.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, The Johns Hopkins University, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801498" target="_blank"〉PubMed〈/a〉