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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-20086-3

2041-1723

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 N. Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney Hornsby, Akua Acheampong, Austen Grooms, Amanda M. 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 Hoan 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 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 G. Montgomery, Wayne H-H Sheu, Ren-Hua Chung, Karen Schwander, Mehdi 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 V. Smith, Tom Blackwell, Daniel Taliun, Sebastian Zöllner, 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 Olav Åsvold, Michael Boehnke, Sekar Kathiresan, Gonçalo R. Abecasis, Y. Eugene Chen, Cristen J. Willer, Kristian Hveem,

Liver Disease Diagnosis and Treatment

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.