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

Authors

Jonas B. Nielsen
Oren Rom
Ida Surakka
Sarah E. Graham
Wei Zhou
Tanmoy Roychowdhury
Lars G. Fritsche
John Blangero, The University of Texas Rio Grande Valley
Joanne E. Curran, The University of Texas Rio Grande Valley
Juan M. Peralta, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

12-18-2020

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.

Comments

© The Author(s) 2020

Recommended Citation

Nielsen, J. B., Rom, O., Surakka, I., Graham, S. E., Zhou, W., Roychowdhury, T., Fritsche, L. G., Gagliano Taliun, S. A., Sidore, C., Liu, Y., Gabrielsen, M. E., Skogholt, A. H., Wolford, B., Overton, W., Zhao, Y., Chen, J., Zhang, H., Hornsby, W. E., Acheampong, A., Grooms, A., … Hveem, K. (2020). Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nature communications, 11(1), 6417. https://doi.org/10.1038/s41467-020-20086-3

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Nature Communications

DOI

10.1038/s41467-020-20086-3

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics