Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

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Abstract

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Abstract

Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.

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The incidence of congenital heart disease.

Julien Hoffman, Samuel Kaplan (2002)

This study was designed to determine the reasons for the variability of the incidence of congenital heart disease (CHD), estimate its true value and provide data about the incidence of specific major forms of CHD. The incidence of CHD in different studies varies from about 4/1,000 to 50/1,000 live births. The relative frequency of different major forms of CHD also differs greatly from study to study. In addition, another 20/1,000 live births have bicuspid aortic valves, isolated anomalous lobar pulmonary veins or a silent patent ductus arteriosus. The incidences reported in 62 studies published after 1955 were examined. Attention was paid to the ways in which the studies were conducted, with special reference to the increased use of echocardiography in the neonatal nursery. The total incidence of CHD was related to the relative frequency of ventricular septal defects (VSDs), the most common type of CHD. The incidences of individual major forms of CHD were determined from 44 studies. The incidence of CHD depends primarily on the number of small VSDs included in the series, and this number in turn depends upon how early the diagnosis is made. If major forms of CHD are stratified into trivial, moderate and severe categories, the variation in incidence depends mainly on the number of trivial lesions included. The incidence of moderate and severe forms of CHD is about 6/1,000 live births (19/1,000 live births if the potentially serious bicuspid aortic valve is included), and of all forms increases to 75/1,000 live births if tiny muscular VSDs present at birth and other trivial lesions are included. Given the causes of variation, there is no evidence for differences in incidence in different countries or times.

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GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.

Vidu Garg, Irfan S Kathiriya, Robert Barnes … (2003)

Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.

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Incidence of aortic complications in patients with bicuspid aortic valves.

Hector Michelena, Amber Khanna, Douglas Mahoney … (2011)

Bicuspid aortic valve (BAV), the most common congenital heart defect, has been thought to cause frequent and severe aortic complications; however, long-term, population-based data are lacking. To determine the incidence of aortic complications in patients with BAV in a community cohort and in the general population. In this retrospective cohort study, we conducted comprehensive assessment of aortic complications of patients with BAV living in a population-based setting in Olmsted County, Minnesota. We analyzed long-term follow-up of a cohort of all Olmsted County residents diagnosed with definite BAV by echocardiography from 1980 to 1999 and searched for aortic complications of patients whose bicuspid valves had gone undiagnosed. The last year of follow-up was 2008-2009. Thoracic aortic dissection, ascending aortic aneurysm, and aortic surgery. The cohort included 416 consecutive patients with definite BAV diagnosed by echocardiography, mean (SD) follow-up of 16 (7) years (6530 patient-years). Aortic dissection occurred in 2 of 416 patients; incidence of 3.1 (95% CI, 0.5-9.5) cases per 10,000 patient-years, age-adjusted relative-risk 8.4 (95% CI, 2.1-33.5; P = .003) compared with the county's general population. Aortic dissection incidences for patients 50 years or older at baseline and bearers of aortic aneurysms at baseline were 17.4 (95% CI, 2.9-53.6) and 44.9 (95% CI, 7.5-138.5) cases per 10,000 patient-years, respectively. Comprehensive search for aortic dissections in undiagnosed bicuspid valves revealed 2 additional patients, allowing estimation of aortic dissection incidence in bicuspid valve patients irrespective of diagnosis status (1.5; 95% CI, 0.4-3.8 cases per 10,000 patient-years), which was similar to the diagnosed cohort. Of 384 patients without baseline aneurysms, 49 developed aneurysms at follow-up, incidence of 84.9 (95% CI, 63.3-110.9) cases per 10,000 patient-years and an age-adjusted relative risk 86.2 (95% CI, 65.1-114; P <.001 compared with the general population). The 25-year rate of aortic surgery was 25% (95% CI, 17.2%-32.8%). In the population of patients with BAV, the incidence of aortic dissection over a mean of 16 years of follow-up was low but significantly higher than in the general population.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 25 May 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 15481

Affiliations

[1 ]Department of Cardiac Surgery, University of Michigan , Ann Arbor, Michigan 48109, USA

[2 ]Frankel Cardiovascular Center, University of Michigan , Ann Arbor, Michigan 48109, USA

[3 ]Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, Michigan 48109, USA

[4 ]Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, USA

[5 ]Department of Anesthesiology, University of Michigan , Ann Arbor, Michigan 48109, USA

[6 ]Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, USA

[7 ]Montreal Heart Institute , Montreal, Quebec, Canada HIT 1C8

[8 ]Department of Medicine, Université de Montréal , Montreal, Quebec, Canada QC H3T 1J4

[9 ]Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet , Stockholm SE-171 76, Sweden

[10 ]Center for Biological Sequence Analysis, Technical University of Denmark , Copenhagen DK-2800, Denmark

[11 ]Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School , Houston, Texas 77030, USA

[12 ]The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai , New York, New York 10029, USA

[13 ]Department of Biostatistics, University of Michigan , Ann Arbor, Michigan 48109, USA

[14 ]Norwegian University of Science and Technology , Trondheim 7491, Norway

[15 ]Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor, Michigan 48105, USA

[16 ]Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet , Stockholm SE-171 76, Sweden

[17 ]Department of Human Genetics, University of Michigan , Ann Arbor, Michigan 48109, USA

[18 ]Institute of Genetic Medicine, Newcastle University , Newcastle Upon Tyne NE1 3BZ, UK

[19 ]Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester , Manchester M13 9PL, UK

[20 ]Manchester Heart Centre, Central Manchester University Hospitals NHS Foundation Trust , Manchester M13 9WL, UK

[21 ]The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai , New York, New York 10029, USA

Author notes

[a ] boya@ 123456med.umich.edu

[b ] cristen@ 123456umich.edu

[*]

These authors contributed equally to this work

[†]

These authors jointly supervised this work

Author information

Jonas B. Nielsen http://orcid.org/0000-0002-6654-2852

Lars Fritsche http://orcid.org/0000-0002-2110-1690

Gregory A. Farnum http://orcid.org/0000-0002-0192-8252

Alan P. Boyle http://orcid.org/0000-0002-2081-1105

Cristen J. Willer http://orcid.org/0000-0001-5645-4966

Article

Publisher Item ID: ncomms15481

DOI: 10.1038/ncomms15481

PMC ID: 5458508

PubMed ID: 28541271

SO-VID: c752f98e-dd51-4c6f-b131-d1eaed20a52b

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History

Date received : 05 October 2016

Date accepted : 31 March 2017

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Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

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Regulatory T cell (Treg) therapy

Most cited references 48

The incidence of congenital heart disease.

GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.

Incidence of aortic complications in patients with bicuspid aortic valves.

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Cited by 37

Most referenced authors 2,045