{"doi":"10.1101/2020.04.23.20076208","title":"Genome-Wide Meta-Analysis Validates a Role for <i>S1PR1</i> in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy","abstract":"Abstract Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 ( S1PR1 encoding S1PR 1 ; e . g ., rs74497159, β CALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), β CALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); P META = 3.62×10 −7 ) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR 1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR 1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.","journal":"medRxiv","year":2020,"id":124828,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":330445,"name":"Chenling Xiong","orcid":null,"position":1,"is_corresponding":false},{"id":357666,"name":"Carol Ho","orcid":null,"position":2,"is_corresponding":false},{"id":356676,"name":"Taisei Mushiroda","orcid":"0000-0002-4139-8794","position":3,"is_corresponding":false},{"id":356677,"name":"J Chen","orcid":"0000-0003-2852-7667","position":4,"is_corresponding":false},{"id":279185,"name":"Flora Mulkey","orcid":"0000-0003-0760-2648","position":5,"is_corresponding":false},{"id":94634,"name":"Dongbing Lai","orcid":"0000-0001-7803-580X","position":6,"is_corresponding":false},{"id":107121,"name":"Bryan P. Schneider","orcid":"0000-0003-1868-7739","position":7,"is_corresponding":false},{"id":233916,"name":"Sara R. Rashkin","orcid":"0000-0001-5542-6891","position":8,"is_corresponding":false},{"id":233930,"name":"John S. Witte","orcid":"0000-0003-0146-1434","position":9,"is_corresponding":false},{"id":357667,"name":"Paula N. Friedman","orcid":null,"position":10,"is_corresponding":false},{"id":356678,"name":"Mark J. Ratain","orcid":"0000-0002-0938-4392","position":11,"is_corresponding":false},{"id":32979,"name":"Howard L. McLeod","orcid":"0000-0002-9004-9232","position":12,"is_corresponding":false},{"id":34069,"name":"Hope S. Rugo","orcid":"0000-0001-6710-4814","position":13,"is_corresponding":false},{"id":263415,"name":"Lawrence N. 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Chua","orcid":null,"position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:15:11.632153Z","pmid":null,"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":[]}