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Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease

Authors :
Gregory J.M. Zajac
Jerome I. Rotter
Rasika A. Mathias
Vivek Rai
David Schlessinger
Tanmoy Roychowdhury
Yuhao Liu
Kathleen C. Barnes
Maiken Elvestad Gabrielsen
John Blangero
Russell P. Tracy
Xiuqing Guo
Albert V. Smith
Mari Løset
Luis Villacorta
Anita Pandit
Xingnan Li
Kent D. Taylor
Anne Heidi Skogholt
Seunggeun Lee
Brooke N. Wolford
Allison E. Ashley-Koch
Scott T. Weiss
Yingze Zhang
Akua Acheampong
Seung Hoan Choi
Steven A. Lubitz
Ketian Yu
Ren-Hua Chung
Jill M. Johnsen
Seyed Mehdi Nouraie
Lars G. Fritsche
Lisa R. Yanek
Yii Der Chen
Austen Grooms
Jessica Lasky-Su
Ida Surakka
Pradeep Natarajan
Michael Boehnke
Lukas Forer
Victor R. Gordeuk
Hyun Min Kang
Whitney E. Hornsby
Stella Aslibekyan
Wayne Huey-Herng Sheu
Ben Michael Brumpton
Sarah A Gagliano Taliun
Patrick T. Ellinor
Francesco Cucca
Karen Schwander
Patricia A. Peyser
Lewis C. Becker
Rebecca D. Jackson
Joanne E. Curran
Jonathon LeFaive
Sebastian Schoenherr
Marguerite R. Irvin
Sarah E. Graham
Eugene R. Bleecker
Solomon K. Musani
Michelle Daya
Alexander P. Reiner
Adolfo Correa
William Overton
Vivien A. Sheehan
Oddgeir L. Holmen
Cristen J. Willer
Bertha A. Hildalgo
Christian Fuchsberger
Chad M. Brummett
Sachin Kheterpal
Matthew Zawistowski
Kristian Hveem
Sekar Kathiresan
James G. Wilson
Marilyn J. Telen
Ramachandran S. Vasan
Bjørn Olav Åsvold
Donna K. Arnett
Sebastian Zöllner
Wei Zhou
Nicholette D. Palmer
Gonçalo R. Abecasis
Jennifer A. Smith
L. Adrienne Cupples
Nicholas M. Rafaels
Lawrence F. Bielak
Barbara A. Konkle
Charles Kooperberg
C Sidore
Juan M. Peralta
Jifeng Zhang
Daniel Taliun
Deborah A. Meyers
Stephen S. Rich
Sayantan Das
Jonas B. Nielsen
Thomas W. Blackwell
Oren Rom
Amanda Schaefer
Y. Eugene Chen
Courtney G. Montgomery
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SUMMARYCardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1Lowering circulating lipids is an important treatment strategy to reduce risk.2,3However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5×) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g.APOB,LPL). A novel LoF variant,ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3×10−8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing ofZNF529in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition ofZNF529or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....a9ab439754e92e14817883bdadc485f8
Full Text :
https://doi.org/10.1101/597377