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

Pubmed ID: 33339817

Pubmed Central ID: PMC7749177

Journal: Nature communications

Publication Date: Dec. 18, 2020

Affiliation: Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway. kristian.hveem@ntnu.no.

MeSH Terms: Humans, Cardiovascular Diseases, Genome-Wide Association Study, Lipids, Genome, Human, Liver, Biological Specimen Banks, United Kingdom, Gene Silencing, Gene Targeting, Loss of Function Mutation, Molecular Targeted Therapy, Phenomics, Receptors, LDL

Grants: R01 HL120393, R01 HL109946, R01 DK062370, U01 DK062370, R01 HL117626, N01AG12109, R01 HL139731, R35 HL135824, HHSN271201100005C, R01 HL130705, K08 HL140203, T32 HG000040, R01 HL123333, R01 HL138139, K99 HL150233, R01 AI132476, R01 HL137214, R01 HL068878, R01 HL127564

Authors: Telen MJ, Zhang Y, Schlessinger D, Abecasis GR, Tracy RP, Vasan RS, Lee S, Chen J, Zhang H, Li X, Zhang J, Guo X, Zhao Y, Smith A, Reiner AP, Rich SS, Jackson RD, Taylor KD, Lubitz SA, Rotter JI, Wilson JG, Cupples LA, Correa A, Kooperberg C, Kathiresan S, Musani SK, Liu Y, Arnett DK, Chen YD, Aslibekyan S, Irvin MR, Smith JA, Schwander K, Blangero J, Hveem K, Willer CJ, Boehnke M, Kang HM, Fuchsberger C, Taliun D, Sidore C, Surakka I, Sheu WH, Palmer ND, Bielak LF, Peyser PA, Cucca F, Konkle BA, Ashley-Koch AE, Gordeuk VR, Nielsen JB, Rom O, Graham SE, Zhou W, Roychowdhury T, Fritsche LG, Gagliano Taliun SA, Gabrielsen ME, Skogholt AH, Wolford B, Overton W, Hornsby WE, Acheampong A, Grooms A, Schaefer A, Zajac GJM, Villacorta L, Brumpton B, Løset M, Rai V, Lundegaard PR, Olesen MS, Choi SH, Ellinor PT, Barnes KC, Daya M, Rafaels N, Weiss ST, Lasky-Su J, Mathias RA, Yanek LR, Becker LC, Hidalgo BA, Johnsen JM, Sheehan VA, Curran JE, Peralta JM, Montgomery C, Chung RH, Nouraie SM, Bleecker ER, Meyers DA, Das S, Yu K, LeFaive J, Blackwell T, Zollner S, Forer L, Schoenherr S, Pandit A, Zawistowski M, Kheterpal S, Brummett CM, Natarajan P, Holmen OL, Åsvold BO, Chen YE

Cite As: 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, Hveem K. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nat Commun 2020 Dec 18;11(1):6417.

Studies:

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<sup>-8</sup>) 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.