{"doi":"10.17615/sdjx-hp22","title":"The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function","abstract":"High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.","journal":"UNC Libraries","year":2020,"id":144153,"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":0.9616,"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":525133,"name":"Hua Tang","orcid":"0000-0002-5757-4123","position":1,"is_corresponding":false},{"id":612660,"name":"Tao Feng","orcid":"0000-0002-8583-1801","position":2,"is_corresponding":false},{"id":481312,"name":"Yajuan Wang","orcid":"0000-0002-3284-9012","position":3,"is_corresponding":false},{"id":579948,"name":"Sung, Yun Ju","orcid":null,"position":4,"is_corresponding":false},{"id":21837,"name":"Bamidele O. Tayo","orcid":"0000-0002-2277-3958","position":5,"is_corresponding":false},{"id":368599,"name":"Xiaofeng Zhu","orcid":"0000-0003-0037-411X","position":6,"is_corresponding":false},{"id":130784,"name":"Richard S. Cooper","orcid":null,"position":7,"is_corresponding":false},{"id":317,"name":"Ting-Wei Mu","orcid":"0000-0002-6419-9296","position":8,"is_corresponding":false},{"id":612661,"name":"Anupam Bandyopadhyay","orcid":"0000-0002-3221-0315","position":9,"is_corresponding":false},{"id":456240,"name":"Jianmin Gao","orcid":"0000-0002-9830-3813","position":10,"is_corresponding":false},{"id":517692,"name":"Robert C. Elston","orcid":"0000-0002-4743-8531","position":11,"is_corresponding":false},{"id":24742,"name":"Nora Franceschini","orcid":"0009-0001-8346-3662","position":12,"is_corresponding":false},{"id":48175,"name":"SCOTT M. WILLIAMS","orcid":"0000-0002-4835-9544","position":13,"is_corresponding":false},{"id":17003,"name":"Heming Wang","orcid":"0000-0002-1486-7495","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:17:45.339291Z","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":[]}