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.
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We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research has been conducted using the UK Biobank Resource under application number 24460. The K.G. Jebesen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology (NTNU) and Central Norway Regional Health Authority. Whole-genome sequencing for the HUNT Study was funded by HL109946. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). J.B.N. is supported by grants from the Danish Heart Foundation (16-R107-A6779) and the Lundbeck Foundation (R220-2016-1434). O.R. is supported by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) grant K99HL150233, American Heart Association Postdoctoral Fellowship 19POST34380224, and the Michigan-Israel Partnership Research Grant. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. L.V. is supported by NIH grant R01-HL123333. P.N. is supported by NIH grant K08-HL140203. J.Z. is supported by NIH grant R01-HL138139. Y.E.C is supported by NIH grants R01-HL068878 and R01-HL137214. C.J.W. is supported by NIH grants R35-HL135824, R01-HL127564, R01-HL117626-02-S1, and R01-HL130705. The SardiNIA research is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) (contracts N01-AG-1-2109 and HHSN271201100005C). This work is also supported by the National Institutes of Health (NHLBI grant HL117626).
All relevant data supporting the key findings of this study are available within the article and its Supplementary Information or Source data files or from the corresponding author upon reasonable request. The genome-wide summary association statistics are available for download at http://csg.sph.umich.edu/willer/public/hunt-lipids-liver-2020/ or at http://jenger.riken.jp/en/ for data related to Biobank Japan. The raw RNA sequence reads (accession number PRJNA549711) are available for download at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA549711/. Source data are provided with this paper.
The source data is also available for download as the additional file listed at the end of this record.
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.; and Arnett, Donna K., "Loss-of-Function Genomic Variants Highlight Potential Therapeutic Targets for Cardiovascular Disease" (2020). Epidemiology Faculty Publications. 69.
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