Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Aorta / metabolism Aortic Aneurysm, Thoracic / genetics Case-Control Studies Caspase 3 / genetics Diabetes Mellitus, Type 2 / genetics Endothelial Cells / metabolism Gene Expression Regulation Genome, Human Genome-Wide Association Study Humans Introns Michigan Muscle, Smooth, Vascular / metabolism Mutation Proto-Oncogene Proteins c-bcl-2 / genetics Quantitative Trait Loci Transcription Factor 7-Like 2 Protein / genetics bcl-2-Associated X Protein / genetics
GWAS TCF7L2 VSMC apoptosis regulatory variant thoracic aortic aneurysm

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
02 09 2021
Historique:
received: 04 03 2021
accepted: 18 06 2021
pubmed: 16 7 2021
medline: 16 9 2021
entrez: 15 7 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ajhg.2021.06.016 PMID: 34265237 PMC: PMC8456156
pubmed: 34265237
pii: S0002-9297(21)00240-8
doi: 10.1016/j.ajhg.2021.06.016
pmc: PMC8456156
pii:
doi:

Substances chimiques

BAX protein, human 0
BCL2 protein, human 0
Proto-Oncogene Proteins c-bcl-2 0
TCF7L2 protein, human 0
Transcription Factor 7-Like 2 Protein 0
bcl-2-Associated X Protein 0
CASP3 protein, human EC 3.4.22.-
Caspase 3 EC 3.4.22.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1578-1589

Subventions

Organisme : NHGRI NIH HHS
ID : T32 HG010464
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135824
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151776
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001780
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL130614
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142023
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141891
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL109942
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138139
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137214
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL109946
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147527
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122664
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134569
Pays : United States
Organisme : BLRD VA
ID : I01 BX003362
Pays : United States

Informations de copyright

Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The spouse of C.J.W. is an employee of Regeneron. All other authors declare no competing interests.

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Auteurs

Tanmoy Roychowdhury (T)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Haocheng Lu (H)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Whitney E Hornsby (WE)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Bradley Crone (B)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

Gao T Wang (GT)

Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

Dong-Chuan Guo (DC)

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.

Anoop K 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.

Poornima Devineni (P)

Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA.

Maoxuan 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.

Wei 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, Cambridge, MA 02142, USA.

Sarah E Graham (SE)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Brooke N Wolford (BN)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

Ida Surakka (I)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Zhenguo Wang (Z)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Lin Chang (L)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Jifeng Zhang (J)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Michael 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.

Chad M Brummett (CM)

Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.

Tori L Melendez (TL)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Michael J Shea (MJ)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Karen Meekyong Kim (KM)

Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

G Michael Deeb (GM)

Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Himanshu J Patel (HJ)

Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Jonathan Eliason (J)

Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Kim A Eagle (KA)

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Bo Yang (B)

Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Santhi K 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.

Ben 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 Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norway.

Bjørn Olav 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, Norway; Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7030, Norway.

Anne Heidi 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.

Kristian 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, Norway.

Saiju 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.

Derek 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.

Philip S 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.

Scott M 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.

Suzanne M 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.

Dianna M Milewicz (DM)

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.

Y Eugene 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.

Minerva T 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.

Cristen J 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, USA. Electronic address: cristen@umich.edu.

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Classifications MeSH

questionsmedicales.fr › Système cardiovasculaire › Vaisseaux sanguins › Artères › Aorte › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Maladies de l'aorte › Anévrysme de l'aorte › Anévrysme de l'aorte thoracique › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Caspases › Caspases effectrices › Caspase-3 › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Introns › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Régions géographiques › Amériques › Amérique du Nord › États-Unis › États du Centre-Ouest des États-Unis › Michigan › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Tissus › Muscles › Muscles lisses › Muscles lisses vasculaires › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-bcl-2 › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription TCF › Protéine-2 de type facteur-7 de transcription › Regulatory variants in TCF7L2 are associated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Protéine Bax › Regulatory variants in TCF7L2 are associated...