Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits.

Cardiovascular Diseases / blood Cholesterol / blood Genomics Genotype Humans Mutation Triglycerides / blood
Cardiovascular traits Electronic Medical Records Genetic association Integrative data analysis Loss-of-function variant Target identification and validation

Journal

BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628

Informations de publication

Date de publication:
25 07 2019
Historique:
entrez: 27 7 2019
pubmed: 28 7 2019
medline: 9 6 2020
Statut: epublish

Résumé

Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

Sections du résumé

BACKGROUND
Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.
RESULTS
We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.
CONCLUSION
In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

Identifiants

DOI: 10.1186/s12920-019-0542-3 PMID: 31345219 PMC: PMC6657044
pubmed: 31345219
doi: 10.1186/s12920-019-0542-3
pii: 10.1186/s12920-019-0542-3
pmc: PMC6657044
doi:

Substances chimiques

Triglycerides 0
Cholesterol 97C5T2UQ7J

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

108

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL125863
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL135289
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA189201
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130423
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000067
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK098294
Pays : United States
Organisme : NCATS NIH HHS
ID : R21 TR001739
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL111339
Pays : United States

Commentaires et corrections

Type : ErratumIn

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Auteurs

Benjamin S Glicksberg (BS)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, 94158, CA, USA.

Letizia Amadori (L)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Cardiovascular Research Center and Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Nicholas K Akers (NK)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Katyayani Sukhavasi (K)

Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia.

Oscar Franzén (O)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Clinical Gene Networks AB, Jungfrugatan 10, 114 44, Stockholm, Sweden.
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Novum, 14157, Huddinge, Sweden.

Li Li (L)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Gillian M Belbin (GM)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Kristin L Ayers (KL)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Sema4, a Mount Sinai venture, Stamford, CT, 06902, USA.

Khader Shameer (K)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Marcus A Badgeley (MA)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Kipp W Johnson (KW)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Ben Readhead (B)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Bruce J Darrow (BJ)

Cardiovascular Research Center and Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Eimear E Kenny (EE)

Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Christer Betsholtz (C)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden.

Raili Ermel (R)

Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406, Tartu, Estonia.

Josefin Skogsberg (J)

Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset Huddinge, 141 86, Stockholm, Sweden.

Arno Ruusalepp (A)

Clinical Gene Networks AB, Jungfrugatan 10, 114 44, Stockholm, Sweden.
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden.

Eric E Schadt (EE)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Clinical Gene Networks AB, Jungfrugatan 10, 114 44, Stockholm, Sweden.
Sema4, a Mount Sinai venture, Stamford, CT, 06902, USA.

Joel T Dudley (JT)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Health Policy and Research, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Hongxia Ren (H)

Department of Pediatrics, Herman B Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Stark Neurosciences Research Institute, Indiana University, 635 Barnhill Dr., MS2049, Indianapolis, IN, 46202, USA.

Jason C Kovacic (JC)

Cardiovascular Research Center and Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Chiara Giannarelli (C)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Cardiovascular Research Center and Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Shuyu D Li (SD)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. shuyudan.li@mssm.edu.
Sema4, a Mount Sinai venture, Stamford, CT, 06902, USA. shuyudan.li@mssm.edu.

Johan L M Björkegren (JLM)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. johan.bjorkegren@mssm.edu.
Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. johan.bjorkegren@mssm.edu.
Clinical Gene Networks AB, Jungfrugatan 10, 114 44, Stockholm, Sweden. johan.bjorkegren@mssm.edu.
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset Huddinge, 141 86, Stockholm, Sweden. johan.bjorkegren@mssm.edu.

Rong Chen (R)

Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. rong.chen@mssm.edu.
Sema4, a Mount Sinai venture, Stamford, CT, 06902, USA. rong.chen@mssm.edu.

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Classifications MeSH

questionsmedicales.fr › Maladies cardiovasculaires › Integrative analysis of loss-of-function...
questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Integrative analysis of loss-of-function...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Integrative analysis of loss-of-function...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Integrative analysis of loss-of-function...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Integrative analysis of loss-of-function...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Integrative analysis of loss-of-function...
questionsmedicales.fr › Lipides › Glycérides › Triglycéride › Integrative analysis of loss-of-function...