{"doi":"10.1101/2025.06.05.25329066","title":"The Evolution of Primary Aldosteronism and the Role of Norrin","abstract":"Primary aldosteronism (PA) is renin-independent aldosteronism that causes hypertension and cardiovascular disease. In this human physiology study, deep-phenotyping maneuvers were conducted to characterize the spectrum of Subclinical PA (SubPA) in normotensive people, along with measurement of the proteomic evolution of PA as it spanned across the continuum of SubPA and in people with clinically overt PA. Differential abundance and dose-dependent aldosterone trend analyses identified a progressive proteomic signature that paralleled the severity of renin-independent aldosteronism that was enriched for cardiovascular disease pathways, including inflammation, redox imbalance, and vascular remodeling. Following multiple in vivo testing maneuvers to modulate aldosterone physiology, Norrin, a Wnt/β-catenin ligand previously identified as an inheritable risk locus for PA, was robustly validated. Candidate-gene validations in a separate cohort of participants that had undergone extensive in vivo aldosterone phenotyping identified NDP variants that were reproducibly associated with multiple physiologic aldosterone traits that were supported by adrenal eQTL data. These findings demonstrate that the clinical spectrum of PA originates in normotensive people and is characterized by progressive proteomic signatures involved in the pathogenesis of cardiovascular disease. Moreover, these convergent proteomic, physiologic, and genetic findings establish Norrin as a novel mediator in the pathogenesis of PA.","journal":"medRxiv","year":2025,"id":555604,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":521214,"name":"Mahyar Heydarpour","orcid":"0000-0002-5741-367X","position":1,"is_corresponding":false},{"id":1366878,"name":"Cheng‐Hsuan Tsai","orcid":"0000-0003-2859-5117","position":2,"is_corresponding":false},{"id":301182,"name":"Jenifer M. Brown","orcid":"0000-0002-6647-639X","position":3,"is_corresponding":false},{"id":729665,"name":"Andrew J Newman","orcid":"0000-0002-8326-1964","position":4,"is_corresponding":false},{"id":1371427,"name":"Sanan Mahrokhian","orcid":null,"position":5,"is_corresponding":false},{"id":1370885,"name":"Isabelle Hanna","orcid":"0009-0009-5968-1406","position":6,"is_corresponding":false},{"id":1205371,"name":"Brooke Honzel","orcid":"0009-0005-2824-903X","position":7,"is_corresponding":false},{"id":1205369,"name":"Laura C Tsai","orcid":"0009-0008-5344-2589","position":8,"is_corresponding":false},{"id":34473,"name":"Sushrut S. Waikar","orcid":"0000-0003-4004-326X","position":9,"is_corresponding":false},{"id":308995,"name":"Kosuke Inoue","orcid":"0000-0001-9614-8103","position":10,"is_corresponding":false},{"id":1453862,"name":"Maria‐Christina Zennaro","orcid":"0000-0001-5449-9191","position":11,"is_corresponding":false},{"id":369854,"name":"Richard J. Auchus","orcid":"0000-0001-6815-6181","position":12,"is_corresponding":false},{"id":364718,"name":"Adina F. Turcu","orcid":"0000-0001-9831-6190","position":13,"is_corresponding":false},{"id":433898,"name":"Jonathan S. Williams","orcid":"0000-0001-7152-765X","position":14,"is_corresponding":false},{"id":461530,"name":"Barry Sacks","orcid":"0000-0003-0297-8507","position":15,"is_corresponding":false},{"id":461529,"name":"Marwan Moussa","orcid":"0000-0003-3462-7007","position":16,"is_corresponding":false},{"id":263020,"name":"Anand Vaidya","orcid":"0000-0002-0314-9252","position":17,"is_corresponding":false},{"id":1354887,"name":"Stéfanie Parisien‐La Salle","orcid":"0000-0001-5960-4181","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:59.329539Z","pmid":"40502598","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":[]}