Evidence map›Paper›PMID 39061094›Full record

ArticleGenome medicine2024

Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response.

Elizabeth Theusch, Flora Y Ting, Yuanyuan Qin, Kristen Stevens, Devesh Naidoo, Sarah M King, Neil V Yang, Joseph Orr, Brenda Y Han, Jason G Cyster and 4 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It reports registered trial NCT00451828. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00451828 phase4completed

Cholesterol and Pharmacogenetic Study

Ran2002Enrolled1,000Registered outcomes11Posted comparisons0ConditionsCardiovascular Disease, Coronary Heart Disease, Hypercholesterolemia, HyperlipidemiaArmssimvastatin
PMID 16516587other papers from this trial
Open the trial in the graph
3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Elizabeth TheuschDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA. Elizabeth.Theusch@ucsf.edu.ORCID 0000-0002-5678-759X
Flora Y TingDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Yuanyuan QinDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Kristen StevensDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Devesh NaidooDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Sarah M KingDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Neil V YangDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Joseph OrrDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Brenda Y HanHoward Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
Jason G CysterHoward Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
Yii-Der I ChenThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Ronald M KraussDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Marisa W MedinaDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA. Marisa.Medina@ucsf.edu.

Funding

Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Andrea L Hevener · 2003 to 2026
$40.4M
Pharmacogenomics and Risk of Cardiovascular DiseaseU01HL069757 · NHLBI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI KRAUSS, RONALD M · 2001 to 2009
$24.7M
Pharmacogenomics of Statin TherapyP50GM115318 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI RISCH, NEIL J. · 2015 to 2019
$14.0M
Pharmacogenomics and Risk of Cardiovascular DiseaseU19HL069757 · NHLBI · CHILDREN'S HOSPITAL & RES CTR AT OAKLAND · PI KRAUSS, RONALD M · 2010 to 2014
$12.8M
American Heart Association 12POST10430005American Heart Association 15POST21880006NHLBI NIH HHS U01 HL069757NHLBI NIH HHS U19 HL069757NIDDK NIH HHS P30 DK063491NIGMS NIH HHS P50 GM115318
6 · The paper itself

Abstract

backgroundStatins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.

methodsTo identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335).

resultsThe statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335

conclusionsOur in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

Indexed as

Cholesterol, LDLHydroxymethylglutaryl-CoA Reductase InhibitorsSimvastatinAnimalsCell LineCholesterolClinical Trials as TopicDNA-Binding ProteinsFemaleGene Expression ProfilingHumansMaleMiceMutation, MissenseTranscription FactorsTranscriptomeCholesterolCholesterol, LDLDNA-Binding ProteinsHydroxymethylglutaryl-CoA Reductase InhibitorsSimvastatinTranscription FactorsCholesterolGene expressionLipoproteinLymphoblastoid cell linesMiceRNA-sequencingStatinZinc finger protein 335

Identifiers

PMID39061094
PMCPMC11282643

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.