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

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Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. / Nielsen, Jonas B.; Rom, Oren; Surakka, Ida; Graham, Sarah E.; Zhou, Wei; Roychowdhury, Tanmoy; Fritsche, Lars G.; Taliun, Sarah A. Gagliano; Sidore, Carlo; Liu, Yuhao; Gabrielsen, Maiken E.; Skogholt, Anne Heidi; Wolford, Brooke; Overton, William; Zhao, Ying; Chen, Jin; Zhang, He; Hornsby, Whitney E.; Acheampong, Akua; Grooms, Austen; Schaefer, Amanda; Zajac, Gregory J. M.; Villacorta, Luis; Zhang, Jifeng; Brumpton, Ben; Loset, Mari; Rai, Vivek; Lundegaard, Pia R.; Olesen, Morten S.; Taylor, Kent D.; Palmer, Nicholette D.; Chen, Yii-Der; Choi, Seung H.; Lubitz, Steven A.; Ellinor, Patrick T.; Barnes, Kathleen C.; Daya, Michelle; Rafaels, Nicholas; Weiss, Scott T.; Lasky-Su, Jessica; Tracy, Russell P.; Vasan, Ramachandran S.; Cupples, L. Adrienne; Mathias, Rasika A.; Yanek, Lisa R.; Becker, Lewis C.; Peyser, Patricia A.; Bielak, Lawrence F.; Smith, Jennifer A.; Aslibekyan, Stella.

I: Nature Communications, Bind 11, Nr. 1, 6417, 2020.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Nielsen, JB, Rom, O, Surakka, I, Graham, SE, Zhou, W, Roychowdhury, T, Fritsche, LG, Taliun, SAG, 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, Loset, M, Rai, V, Lundegaard, PR, Olesen, MS, Taylor, KD, Palmer, ND, Chen, Y-D, 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 2020, 'Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease', Nature Communications, bind 11, nr. 1, 6417. https://doi.org/10.1038/s41467-020-20086-3

APA

Nielsen, J. B., Rom, O., Surakka, I., Graham, S. E., Zhou, W., Roychowdhury, T., Fritsche, L. G., Taliun, S. A. G., 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., ... Aslibekyan, S. (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

Vancouver

Nielsen JB, Rom O, Surakka I, Graham SE, Zhou W, Roychowdhury T o.a. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nature Communications. 2020;11(1). 6417. https://doi.org/10.1038/s41467-020-20086-3

Author

Nielsen, Jonas B. ; Rom, Oren ; Surakka, Ida ; Graham, Sarah E. ; Zhou, Wei ; Roychowdhury, Tanmoy ; Fritsche, Lars G. ; Taliun, Sarah A. Gagliano ; Sidore, Carlo ; Liu, Yuhao ; Gabrielsen, Maiken E. ; Skogholt, Anne Heidi ; Wolford, Brooke ; Overton, William ; Zhao, Ying ; Chen, Jin ; Zhang, He ; Hornsby, Whitney E. ; Acheampong, Akua ; Grooms, Austen ; Schaefer, Amanda ; Zajac, Gregory J. M. ; Villacorta, Luis ; Zhang, Jifeng ; Brumpton, Ben ; Loset, Mari ; Rai, Vivek ; Lundegaard, Pia R. ; Olesen, Morten S. ; Taylor, Kent D. ; Palmer, Nicholette D. ; Chen, Yii-Der ; Choi, Seung H. ; Lubitz, Steven A. ; Ellinor, Patrick T. ; Barnes, Kathleen C. ; Daya, Michelle ; Rafaels, Nicholas ; Weiss, Scott T. ; Lasky-Su, Jessica ; Tracy, Russell P. ; Vasan, Ramachandran S. ; Cupples, L. Adrienne ; Mathias, Rasika A. ; Yanek, Lisa R. ; Becker, Lewis C. ; Peyser, Patricia A. ; Bielak, Lawrence F. ; Smith, Jennifer A. ; Aslibekyan, Stella. / Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. I: Nature Communications. 2020 ; Bind 11, Nr. 1.

Bibtex

@article{f3504b889463478e87e1d6c3b9dc0b1b,
title = "Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease",
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=1.3x10(-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. Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.",
keywords = "WIDE ASSOCIATION, THALASSEMIA, METABOLISM, GENERATION, PATHWAYS, EXOME, MODEL, LOCI",
author = "Nielsen, {Jonas B.} and Oren Rom and Ida Surakka and Graham, {Sarah E.} and Wei Zhou and Tanmoy Roychowdhury and Fritsche, {Lars G.} and Taliun, {Sarah A. Gagliano} and Carlo Sidore and Yuhao Liu and Gabrielsen, {Maiken E.} and Skogholt, {Anne Heidi} and Brooke Wolford and William Overton and Ying Zhao and Jin Chen and He Zhang and Hornsby, {Whitney E.} and Akua Acheampong and Austen Grooms and Amanda Schaefer and Zajac, {Gregory J. M.} and Luis Villacorta and Jifeng Zhang and Ben Brumpton and Mari Loset and Vivek Rai and Lundegaard, {Pia R.} and Olesen, {Morten S.} and Taylor, {Kent D.} and Palmer, {Nicholette D.} and Yii-Der Chen and Choi, {Seung H.} and Lubitz, {Steven A.} and Ellinor, {Patrick T.} and Barnes, {Kathleen C.} and Michelle Daya and Nicholas Rafaels and Weiss, {Scott T.} and Jessica Lasky-Su and Tracy, {Russell P.} and Vasan, {Ramachandran S.} and Cupples, {L. Adrienne} and Mathias, {Rasika A.} and Yanek, {Lisa R.} and Becker, {Lewis C.} and Peyser, {Patricia A.} and Bielak, {Lawrence F.} and Smith, {Jennifer A.} and Stella Aslibekyan",
year = "2020",
doi = "10.1038/s41467-020-20086-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

AU - Nielsen, Jonas B.

AU - Rom, Oren

AU - Surakka, Ida

AU - Graham, Sarah E.

AU - Zhou, Wei

AU - Roychowdhury, Tanmoy

AU - Fritsche, Lars G.

AU - Taliun, Sarah A. Gagliano

AU - Sidore, Carlo

AU - Liu, Yuhao

AU - Gabrielsen, Maiken E.

AU - Skogholt, Anne Heidi

AU - Wolford, Brooke

AU - Overton, William

AU - Zhao, Ying

AU - Chen, Jin

AU - Zhang, He

AU - Hornsby, Whitney E.

AU - Acheampong, Akua

AU - Grooms, Austen

AU - Schaefer, Amanda

AU - Zajac, Gregory J. M.

AU - Villacorta, Luis

AU - Zhang, Jifeng

AU - Brumpton, Ben

AU - Loset, Mari

AU - Rai, Vivek

AU - Lundegaard, Pia R.

AU - Olesen, Morten S.

AU - Taylor, Kent D.

AU - Palmer, Nicholette D.

AU - Chen, Yii-Der

AU - Choi, Seung H.

AU - Lubitz, Steven A.

AU - Ellinor, Patrick T.

AU - Barnes, Kathleen C.

AU - Daya, Michelle

AU - Rafaels, Nicholas

AU - Weiss, Scott T.

AU - Lasky-Su, Jessica

AU - Tracy, Russell P.

AU - Vasan, Ramachandran S.

AU - Cupples, L. Adrienne

AU - Mathias, Rasika A.

AU - Yanek, Lisa R.

AU - Becker, Lewis C.

AU - Peyser, Patricia A.

AU - Bielak, Lawrence F.

AU - Smith, Jennifer A.

AU - Aslibekyan, Stella

PY - 2020

Y1 - 2020

N2 - 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=1.3x10(-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. Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

AB - 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=1.3x10(-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. Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

KW - WIDE ASSOCIATION

KW - THALASSEMIA

KW - METABOLISM

KW - GENERATION

KW - PATHWAYS

KW - EXOME

KW - MODEL

KW - LOCI

U2 - 10.1038/s41467-020-20086-3

DO - 10.1038/s41467-020-20086-3

M3 - Journal article

C2 - 33339817

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 6417

ER -

ID: 256276273