Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Jonas B. Nielsen (), Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Amanda Schaefer, Gregory J. M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Nicholette D. Palmer, Yii- Der Chen, Seung H. Choi, Steven A. Lubitz, Patrick T. Ellinor, Kathleen C. Barnes, Michelle Daya, Nicholas Rafaels, Scott T. Weiss, Jessica Lasky-Su, Russell P. Tracy, Ramachandran S. Vasan, L. Adrienne Cupples, Rasika A. Mathias, Lisa R. Yanek, Lewis C. Becker, Patricia A. Peyser, Lawrence F. Bielak, Jennifer A. Smith, Stella Aslibekyan, Bertha A. Hidalgo, Donna K. Arnett, Marguerite R. Irvin, James G. Wilson, Solomon K. Musani, Adolfo Correa, Stephen S. Rich, Xiuqing Guo, Jerome I. Rotter, Barbara A. Konkle, Jill M. Johnsen, Allison E. Ashley-Koch, Marilyn J. Telen, Vivien A. Sheehan, John Blangero, Joanne E. Curran, Juan M. Peralta, Courtney Montgomery, Wayne H-H Sheu, Ren-Hua Chung, Karen Schwander, Seyed M. Nouraie, Victor R. Gordeuk, Yingze Zhang, Charles Kooperberg, Alexander P. Reiner, Rebecca D. Jackson, Eugene R. Bleecker, Deborah A. Meyers, Xingnan Li, Sayantan Das, Ketian Yu, Jonathon LeFaive, Albert Smith, Tom Blackwell, Daniel Taliun, Sebastian Zollner, Lukas Forer, Sebastian Schoenherr, Christian Fuchsberger, Anita Pandit, Matthew Zawistowski, Sachin Kheterpal, Chad M. Brummett, Pradeep Natarajan, David Schlessinger, Seunggeun Lee, Hyun Min Kang, Francesco Cucca, Oddgeir L. Holmen, Bjørn O. Åsvold, Michael Boehnke, Sekar Kathiresan, Goncalo R. Abecasis, Y. Eugene Chen (), Cristen J. Willer () and Kristian Hveem ()
Additional contact information
Jonas B. Nielsen: University of Michigan
Oren Rom: University of Michigan
Ida Surakka: University of Michigan
Sarah E. Graham: University of Michigan
Wei Zhou: Broad Institute of Harvard and MIT
Tanmoy Roychowdhury: University of Michigan
Lars G. Fritsche: University of Michigan
Sarah A. Gagliano Taliun: University of Michigan School of Public Health
Carlo Sidore: Consiglio Nazionale delle Ricerche (CNR)
Yuhao Liu: University of Michigan
Maiken E. Gabrielsen: Norwegian University of Science and Technology, NTNU
Anne Heidi Skogholt: Norwegian University of Science and Technology, NTNU
Brooke Wolford: University of Michigan
William Overton: University of Michigan School of Public Health
Ying Zhao: University of Michigan
Jin Chen: University of Michigan
He Zhang: University of Michigan
Whitney E. Hornsby: University of Michigan
Akua Acheampong: University of Michigan
Austen Grooms: University of Michigan
Amanda Schaefer: University of Michigan
Gregory J. M. Zajac: University of Michigan School of Public Health
Luis Villacorta: University of Michigan
Jifeng Zhang: University of Michigan
Ben Brumpton: Norwegian University of Science and Technology, NTNU
Mari Løset: Norwegian University of Science and Technology, NTNU
Vivek Rai: University of Michigan
Pia R. Lundegaard: Copenhagen University Hospital Rigshospitalet
Morten S. Olesen: Copenhagen University Hospital Rigshospitalet
Kent D. Taylor: The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA
Nicholette D. Palmer: Wake Forest School of Medicine
Yii- Der Chen: The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA
Seung H. Choi: Broad Institute of Harvard and MIT
Steven A. Lubitz: Broad Institute of Harvard and MIT
Patrick T. Ellinor: Broad Institute of Harvard and MIT
Kathleen C. Barnes: University of Colorado
Michelle Daya: University of Colorado
Nicholas Rafaels: University of Colorado
Scott T. Weiss: Channing Division of Network Medicine, Department of Medicine Brigham and Women’s Hospital
Jessica Lasky-Su: Channing Division of Network Medicine, Department of Medicine Brigham and Women’s Hospital
Russell P. Tracy: Larner College of Medicine, University of Vermont
Ramachandran S. Vasan: Boston University School of Medicine
L. Adrienne Cupples: Framingham Heart Study
Rasika A. Mathias: Johns Hopkins School of Medicine
Lisa R. Yanek: Johns Hopkins School of Medicine
Lewis C. Becker: Johns Hopkins School of Medicine
Patricia A. Peyser: School of Public Health, University of Michigan
Lawrence F. Bielak: School of Public Health, University of Michigan
Jennifer A. Smith: School of Public Health, University of Michigan
Stella Aslibekyan: The University of Alabama at Birmingham
Bertha A. Hidalgo: The University of Alabama at Birmingham
Donna K. Arnett: Deans Office, College of Public Health, University of Kentucky
Marguerite R. Irvin: The University of Alabama at Birmingham
James G. Wilson: University of Mississippi Medical Center
Solomon K. Musani: Jackson Heart Study
Adolfo Correa: Jackson Heart Study
Stephen S. Rich: University of Virginia
Xiuqing Guo: The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA
Jerome I. Rotter: The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA
Barbara A. Konkle: University of Washington
Jill M. Johnsen: University of Washington
Allison E. Ashley-Koch: Duke University Medical Center
Marilyn J. Telen: Duke University Medical Center
Vivien A. Sheehan: Baylor College of Medicine
John Blangero: University of Texas Rio Grande Valley School of Medicine
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
Juan M. Peralta: University of Texas Rio Grande Valley School of Medicine
Courtney Montgomery: Oklahoma Medical Research Foundation
Wayne H-H Sheu: Taichung Veterans General Hospital
Ren-Hua Chung: National Health Research Institutes
Karen Schwander: Washington University School of Medicine
Seyed M. Nouraie: University of Pittsburgh School of Medicine
Victor R. Gordeuk: University of Illinois at Chicago
Yingze Zhang: University of Pittsburgh School of Medicine
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Rebecca D. Jackson: Ohio State University
Eugene R. Bleecker: Division of Pharmacogenomics University of Arizona
Deborah A. Meyers: Division of Pharmacogenomics University of Arizona
Xingnan Li: University of Arizona
Sayantan Das: University of Michigan
Ketian Yu: University of Michigan School of Public Health
Jonathon LeFaive: University of Michigan School of Public Health
Albert Smith: University of Michigan School of Public Health
Tom Blackwell: University of Michigan School of Public Health
Daniel Taliun: University of Michigan School of Public Health
Sebastian Zollner: University of Michigan School of Public Health
Lukas Forer: University of Arizona
Sebastian Schoenherr: Medical University of Innsbruck
Christian Fuchsberger: University of Michigan School of Public Health
Anita Pandit: University of Michigan School of Public Health
Matthew Zawistowski: University of Michigan School of Public Health
Sachin Kheterpal: University of Michigan
Chad M. Brummett: University of Michigan
Pradeep Natarajan: Broad Institute of Harvard and MIT
David Schlessinger: US National Institutes of Health
Seunggeun Lee: University of Michigan School of Public Health
Hyun Min Kang: University of Michigan School of Public Health
Francesco Cucca: Consiglio Nazionale delle Ricerche (CNR)
Oddgeir L. Holmen: Norwegian University of Science and Technology, NTNU
Bjørn O. Åsvold: Norwegian University of Science and Technology, NTNU
Michael Boehnke: University of Michigan School of Public Health
Sekar Kathiresan: Harvard Medical School
Goncalo R. Abecasis: University of Michigan School of Public Health
Y. Eugene Chen: University of Michigan
Cristen J. Willer: University of Michigan
Kristian Hveem: Norwegian University of Science and Technology, NTNU

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Date: 2020
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DOI: 10.1038/s41467-020-20086-3

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