{"doi":"10.1101/2023.06.14.544860","title":"Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":408635,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9664,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT00451828"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1188261,"name":"Flora Ting","orcid":null,"position":1,"is_corresponding":false},{"id":1187825,"name":"Yuanyuan Qin","orcid":"0000-0002-8168-3573","position":2,"is_corresponding":false},{"id":1188262,"name":"Kristen N. Stevens","orcid":null,"position":3,"is_corresponding":false},{"id":1188263,"name":"Devesh Naidoo","orcid":null,"position":4,"is_corresponding":false},{"id":438055,"name":"Sarah M. King","orcid":"0000-0002-3907-8804","position":5,"is_corresponding":false},{"id":1188264,"name":"Neil Yang","orcid":null,"position":6,"is_corresponding":false},{"id":1135413,"name":"Joseph Orr","orcid":null,"position":7,"is_corresponding":false},{"id":90224,"name":"Yuyuan Han","orcid":"0000-0002-3212-875X","position":8,"is_corresponding":false},{"id":235419,"name":"Jason G. Cyster","orcid":"0000-0002-4735-9745","position":9,"is_corresponding":false},{"id":493033,"name":"Yii‐Der I. Chen","orcid":null,"position":10,"is_corresponding":false},{"id":11276,"name":"Jerome I. Rotter","orcid":"0000-0001-7191-1723","position":11,"is_corresponding":false},{"id":364930,"name":"Ronald M. Krauss","orcid":"0000-0002-1238-3489","position":12,"is_corresponding":false},{"id":471244,"name":"Marisa W. Medina","orcid":"0000-0002-3631-0129","position":13,"is_corresponding":false},{"id":493032,"name":"Elizabeth Theusch","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:21:18.414003Z","pmid":"37397985","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}