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

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

Nature communications (2020-12-20)

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 Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E Hornsby, Akua Acheampong, Austen Grooms, Amanda 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 H 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 A 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 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

PMID33339817

ZUSAMMENFASSUNG

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.