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

Autor:	Theusch E; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Ting FY; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Qin Y; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Stevens K; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Naidoo D; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., King SM; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Yang N; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Orr J; Department of Pediatrics, University of California San Francisco, Oakland, CA USA., Han BY; Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA USA., Cyster JG; Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA USA., Chen YI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Krauss RM; Department of Pediatrics, University of California San Francisco, Oakland, CA USA.; Department of Medicine, University of California San Francisco, Oakland, CA USA., Medina MW; Department of Pediatrics, University of California San Francisco, Oakland, CA USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 15. Date of Electronic Publication: 2023 Jun 15.
DOI:	10.1101/2023.06.14.544860
Abstrakt:	Background: Statins 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. Methods: To 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 ). Results: The 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 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions: Our 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. Competing Interests: Competing interests The authors declare that they have no competing interests.
Databáze:	MEDLINE
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