Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease
Authors: Nielsen Jonas B. , Rom Oren , Surakka Ida , Graham Sarah E. , Zhou Wei , Roychowdhury Tanmoy , Fritsche Lars G. , Gagliano Taliun Sarah A. , Sidore Carlo , Liu Yuhao , Gabrielsen Maiken E. , Skogholt Anne Heidi , Wolford Brooke , Overton William , Zhao Ying , Chen Jin , Zhang He , Hornsby Whitney E. , Acheampong Akua , Grooms Austen , Schaefer Amanda , Zajac Gregory J. M. , Villacorta Luis , Zhang Jifeng , Brumpton Ben , Løset Mari , Rai Vivek , Lundegaard Pia R. , Olesen Morten S. , Taylor Kent D. , Palmer Nicholette D. , Chen Yii-Der , Choi Seung H. , Lubitz Steven A. , Ellinor Patrick T. , Barnes Kathleen C. , Daya Michelle , Rafaels Nicholas , Weiss Scott T. , Lasky-Su Jessica , Tracy Russell P. , Vasan Ramachandran S. , Cupples L. Adrienne , Mathias Rasika A. , Yanek Lisa R. , Becker Lewis C. , Peyser Patricia A. , Bielak Lawrence F. , Smith Jennifer A. , Aslibekyan Stella , Hidalgo Bertha A. , Arnett Donna K. , Irvin Marguerite R. , Wilson James G. , Musani Solomon K. , Correa Adolfo , Rich Stephen S. , Guo Xiuqing , Rotter Jerome I. , Konkle Barbara A. , Johnsen Jill M. , Ashley-Koch Allison E. , Telen Marilyn J. , Sheehan Vivien A. , Blangero John , Curran Joanne E. , Peralta Juan M. , Montgomery Courtney , Sheu Wayne H-H , Chung Ren-Hua , Schwander Karen , Nouraie Seyed M. , Gordeuk Victor R. , Zhang Yingze , Kooperberg Charles , Reiner Alexander P. , Jackson Rebecca D. , Bleecker Eugene R. , Meyers Deborah A. , Li Xingnan , Das Sayantan , Yu Ketian , LeFaive Jonathon , Smith Albert , Blackwell Tom , Taliun Daniel , Zollner Sebastian , Forer Lukas , Schoenherr Sebastian , Fuchsberger Christian , Pandit Anita , Zawistowski Matthew , Kheterpal Sachin , Brummett Chad M. , Natarajan Pradeep , Schlessinger David , Lee Seunggeun , Kang Hyun Min , Cucca Francesco , Holmen Oddgeir L. , Åsvold Bjørn O. , Boehnke Michael , Kathiresan Sekar , Abecasis Goncalo R. , Chen Y. Eugene , Willer Cristen J. , Hveem Kristian 
Published: December 2020

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.