1. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.
- Author
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Nielsen JB, Rom O, Surakka I, Graham SE, Zhou W, Roychowdhury T, Fritsche LG, Gagliano Taliun SA, Sidore C, Liu Y, Gabrielsen ME, Skogholt AH, Wolford B, Overton W, Zhao Y, Chen J, Zhang H, Hornsby WE, Acheampong A, Grooms A, Schaefer A, Zajac GJM, Villacorta L, Zhang J, Brumpton B, Løset M, Rai V, Lundegaard PR, Olesen MS, Taylor KD, Palmer ND, Chen YD, Choi SH, Lubitz SA, Ellinor PT, Barnes KC, Daya M, Rafaels N, Weiss ST, Lasky-Su J, Tracy RP, Vasan RS, Cupples LA, Mathias RA, Yanek LR, Becker LC, Peyser PA, Bielak LF, Smith JA, Aslibekyan S, Hidalgo BA, Arnett DK, Irvin MR, Wilson JG, Musani SK, Correa A, Rich SS, Guo X, Rotter JI, Konkle BA, Johnsen JM, Ashley-Koch AE, Telen MJ, Sheehan VA, Blangero J, Curran JE, Peralta JM, Montgomery C, Sheu WH, Chung RH, Schwander K, Nouraie SM, Gordeuk VR, Zhang Y, Kooperberg C, Reiner AP, Jackson RD, Bleecker ER, Meyers DA, Li X, Das S, Yu K, LeFaive J, Smith A, Blackwell T, Taliun D, Zollner S, Forer L, Schoenherr S, Fuchsberger C, Pandit A, Zawistowski M, Kheterpal S, Brummett CM, Natarajan P, Schlessinger D, Lee S, Kang HM, Cucca F, Holmen OL, Åsvold BO, Boehnke M, Kathiresan S, Abecasis GR, Chen YE, Willer CJ, and Hveem K
- Subjects
- Biological Specimen Banks, Cardiovascular Diseases blood, Gene Silencing, Gene Targeting, Genome-Wide Association Study, Humans, Lipids blood, Liver metabolism, Phenomics, Receptors, LDL genetics, United Kingdom, Cardiovascular Diseases genetics, Genome, Human, Loss of Function Mutation genetics, Molecular Targeted Therapy
- 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.- Published
- 2020
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