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

By Jonas B Nielsen, Oren Rom, Ida Surakka, Sarah E Graham, Wei Zhou, Lars G. Fritsche, Sarah A Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Tanmoy Roychowdhury, Amanda Schaefer, Gregory JM Zajac, Luis Villacorta, Jifeng Zhang, Ben M Brumpton, Mari Løset, Vivek Rai, Kent 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, Vasan Ramachandran, 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 Hildalgo, Donna K Arnett, Marguerite R Irvin, James G Wilson, Solomon K Musani, Adolfo Correa, Stephen Rich, Xiuqing Guo, Jerome 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 Abecasis, Y Eugene Chen, Cristen J Willer, Kristian Hveem

Posted 02 Apr 2019
bioRxiv DOI: 10.1101/597377

Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally. Lowering circulating lipids is an important treatment strategy to reduce risk. However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders. To 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 (5x) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference pane, 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=1.3x10-8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing of ZNF529 in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition of ZNF529 or 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.

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