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

Author

Listed:
  • Jonas B. Nielsen

    (University of Michigan
    Norwegian University of Science and Technology, NTNU)

  • Oren Rom

    (University of Michigan)

  • Ida Surakka

    (University of Michigan)

  • Sarah E. Graham

    (University of Michigan)

  • Wei Zhou

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    University of Michigan)

  • Tanmoy Roychowdhury

    (University of Michigan)

  • Lars G. Fritsche

    (University of Michigan
    Norwegian University of Science and Technology, NTNU
    University of Michigan School of Public Health)

  • Sarah A. Gagliano Taliun

    (University of Michigan School of Public Health
    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
    University of Michigan School of Public Health)

  • 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
    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
    St. Olav’s Hospital, Trondheim University Hospital)

  • Vivek Rai

    (University of Michigan)

  • Pia R. Lundegaard

    (Copenhagen University Hospital Rigshospitalet
    University of Copenhagen)

  • Morten S. Olesen

    (Copenhagen University Hospital Rigshospitalet
    University of Copenhagen)

  • 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
    Massachusetts General Hospital)

  • Patrick T. Ellinor

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • 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
    Harvard Medical School)

  • Jessica Lasky-Su

    (Channing Division of Network Medicine, Department of Medicine Brigham and Women’s Hospital
    Harvard Medical School)

  • Russell P. Tracy

    (Larner College of Medicine, University of Vermont
    Larner College of Medicine, University of Vermont)

  • Ramachandran S. Vasan

    (Boston University School of Medicine
    Framingham Heart Study)

  • L. Adrienne Cupples

    (Framingham Heart Study
    Boston University School of Public Health)

  • 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
    University of Michigan)

  • Stella Aslibekyan

    (The University of Alabama at Birmingham
    23andMe, Inc.)

  • 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
    Jackson Heart Study)

  • Solomon K. Musani

    (Jackson Heart Study
    University of Mississippi Medical Center)

  • Adolfo Correa

    (Jackson Heart Study
    University of Mississippi Medical Center)

  • 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
    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
    University of Texas Rio Grande Valley School of Medicine)

  • Joanne E. Curran

    (University of Texas Rio Grande Valley School of Medicine
    University of Texas Rio Grande Valley School of Medicine)

  • Juan M. Peralta

    (University of Texas Rio Grande Valley School of Medicine
    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
    University of Washington)

  • 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
    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
    University of Michigan School of Public Health
    Eurac Research)

  • 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
    Massachusetts General Hospital, Harvard Medical School)

  • 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)
    Università degli Studi di Sassari)

  • Oddgeir L. Holmen

    (Norwegian University of Science and Technology, NTNU
    Norwegian University of Science and Technology)

  • Bjørn O. Åsvold

    (Norwegian University of Science and Technology, NTNU
    Norwegian University of Science and Technology
    St. Olavs Hospital, Trondheim University Hospital)

  • Michael Boehnke

    (University of Michigan School of Public Health
    University of Michigan School of Public Health)

  • Sekar Kathiresan

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School
    Broad Institute)

  • Goncalo R. Abecasis

    (University of Michigan School of Public Health
    University of Michigan School of Public Health
    Regeneron Pharmaceuticals)

  • Y. Eugene Chen

    (University of Michigan)

  • Cristen J. Willer

    (University of Michigan
    Norwegian University of Science and Technology, NTNU
    University of Michigan
    University of Michigan)

  • Kristian Hveem

    (Norwegian University of Science and Technology, NTNU
    Norwegian University of Science and Technology
    Levanger Hospital, Nord-Trøndelag Hospital Trust)

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.

Suggested Citation

  • 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 Heid, 2020. "Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20086-3
    DOI: 10.1038/s41467-020-20086-3
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    Cited by:

    1. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    2. Margaret Sunitha Selvaraj & Xihao Li & Zilin Li & Akhil Pampana & David Y. Zhang & Joseph Park & Stella Aslibekyan & Joshua C. Bis & Jennifer A. Brody & Brian E. Cade & Lee-Ming Chuang & Ren-Hua Chung, 2022. "Whole genome sequence analysis of blood lipid levels in >66,000 individuals," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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