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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?=?1.3?×?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.

SUBMITTER: Nielsen JB

PROVIDER: S-EPMC7749177 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Nielsen Jonas B JB Rom Oren O Surakka Ida I Graham Sarah E SE Zhou Wei W Roychowdhury Tanmoy T Fritsche Lars G LG Gagliano Taliun Sarah A SA Sidore Carlo C Liu Yuhao Y Gabrielsen Maiken E ME Skogholt Anne Heidi AH Wolford Brooke B Overton William W Zhao Ying Y Chen Jin J Zhang He H Hornsby Whitney E WE Acheampong Akua A Grooms Austen A Schaefer Amanda A Zajac Gregory J M GJM Villacorta Luis L Zhang Jifeng J Brumpton Ben B Løset Mari M Rai Vivek V Lundegaard Pia R PR Olesen Morten S MS Taylor Kent D KD Palmer Nicholette D ND Chen Yii-Der YD Choi Seung H SH Lubitz Steven A SA Ellinor Patrick T PT Barnes Kathleen C KC Daya Michelle M Rafaels Nicholas N Weiss Scott T ST Lasky-Su Jessica J Tracy Russell P RP Vasan Ramachandran S RS Cupples L Adrienne LA Mathias Rasika A RA Yanek Lisa R LR Becker Lewis C LC Peyser Patricia A PA Bielak Lawrence F LF Smith Jennifer A JA Aslibekyan Stella S Hidalgo Bertha A BA Arnett Donna K DK Irvin Marguerite R MR Wilson James G JG Musani Solomon K SK Correa Adolfo A Rich Stephen S SS Guo Xiuqing X Rotter Jerome I JI Konkle Barbara A BA Johnsen Jill M JM Ashley-Koch Allison E AE Telen Marilyn J MJ Sheehan Vivien A VA Blangero John J Curran Joanne E JE Peralta Juan M JM Montgomery Courtney C Sheu Wayne H-H WH Chung Ren-Hua RH Schwander Karen K Nouraie Seyed M SM Gordeuk Victor R VR Zhang Yingze Y Kooperberg Charles C Reiner Alexander P AP Jackson Rebecca D RD Bleecker Eugene R ER Meyers Deborah A DA Li Xingnan X Das Sayantan S Yu Ketian K LeFaive Jonathon J Smith Albert A Blackwell Tom T Taliun Daniel D Zollner Sebastian S Forer Lukas L Schoenherr Sebastian S Fuchsberger Christian C Pandit Anita A Zawistowski Matthew M Kheterpal Sachin S Brummett Chad M CM Natarajan Pradeep P Schlessinger David D Lee Seunggeun S Kang Hyun Min HM Cucca Francesco F Holmen Oddgeir L OL Åsvold Bjørn O BO Boehnke Michael M Kathiresan Sekar S Abecasis Goncalo R GR Chen Y Eugene YE Willer Cristen J CJ Hveem Kristian K

Nature communications 20201218 1

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 id ...[more]

PMID: 33339817

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Project description:The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.

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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.

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