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Nature Research, Nature Communications, 1(11), 2020

DOI: 10.1038/s41467-020-20086-3



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

Journal article published in 2020 by Jonas B. Nielsen ORCID, Oren Rom, Ida Surakka, Sarah E. Graham ORCID, Wei Zhou ORCID, Tanmoy Roychowdhury, Lars G. Fritsche ORCID, Sarah A. Gagliano Taliun ORCID, Carlo Sidore ORCID, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford ORCID, William Overton, Ying Zhao and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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AbstractPharmaceutical 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.