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Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.
Roychowdhury, Tanmoy; Lu, Haocheng; Hornsby, Whitney E; Crone, Bradley; Wang, Gao T; Guo, Dong-Chuan; Sendamarai, Anoop K; Devineni, Poornima; Lin, Maoxuan; Zhou, Wei; Graham, Sarah E; Wolford, Brooke N; Surakka, Ida; Wang, Zhenguo; Chang, Lin; Zhang, Jifeng; Mathis, Michael; Brummett, Chad M; Melendez, Tori L; Shea, Michael J; Kim, Karen Meekyong; Deeb, G Michael; Patel, Himanshu J; Eliason, Jonathan; Eagle, Kim A; Yang, Bo; Ganesh, Santhi K; Brumpton, Ben; Åsvold, Bjørn Olav; Skogholt, Anne Heidi; Hveem, Kristian; Pyarajan, Saiju; Klarin, Derek; Tsao, Philip S; Damrauer, Scott M; Leal, Suzanne M; Milewicz, Dianna M; Chen, Y Eugene; Garcia-Barrio, Minerva T; Willer, Cristen J.
Affiliation
  • Roychowdhury T; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Lu H; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Hornsby WE; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Crone B; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wang GT; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • Guo DC; Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.
  • Sendamarai AK; Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA; Booz Allen Hamilton, McLean, VA 22102, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Devineni P; Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA.
  • Lin M; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA 02114, USA.
  • Zhou W; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambri
  • Graham SE; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wolford BN; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Surakka I; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wang Z; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Chang L; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zhang J; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mathis M; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Brummett CM; Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Melendez TL; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Shea MJ; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kim KM; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Deeb GM; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Patel HJ; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Eliason J; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Eagle KA; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Yang B; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Ganesh SK; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Brumpton B; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7030, Norway; HUNT Research Center, Department of Publi
  • Åsvold BO; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norw
  • Skogholt AH; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.
  • Hveem K; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norw
  • Pyarajan S; Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Klarin D; Malcolm Randall VA Medical Center, Gainesville, FL 32608, USA; Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32608, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Tsao PS; VA Palo Alto Health Care System, Palo Alto, CA 94304, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5406, USA.
  • Damrauer SM; Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Leal SM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Alzheimer disease and the Aging Brain, Columbia University, NY 10032, USA.
  • Milewicz DM; Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.
  • Chen YE; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Garcia-Barrio MT; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: minerva@med.umich.edu.
  • Willer CJ; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Article de En | MEDLINE | ID: mdl-34265237
ABSTRACT
Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Anévrysme de l'aorte thoracique / Protéines proto-oncogènes c-bcl-2 / Locus de caractère quantitatif / Cellules endothéliales / Diabète de type 2 / Protéine-2 de type facteur-7 de transcription Type d'étude: Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Humans Pays/Région comme sujet: America do norte Langue: En Journal: Am J Hum Genet Année: 2021 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Anévrysme de l'aorte thoracique / Protéines proto-oncogènes c-bcl-2 / Locus de caractère quantitatif / Cellules endothéliales / Diabète de type 2 / Protéine-2 de type facteur-7 de transcription Type d'étude: Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Humans Pays/Région comme sujet: America do norte Langue: En Journal: Am J Hum Genet Année: 2021 Type de document: Article Pays d'affiliation: États-Unis d'Amérique