{"doi":"10.1101/2023.04.07.536073","title":"Analysis of the Combined Effect of rs699 and rs5051 on Angiotensinogen Expression and Hypertension","abstract":"ABSTRACT Hypertension (HTN) involves genetic variability in the renin-angiotensin system and characterizing this variability will help advance precision antihypertensive treatments. We previously reported that angiotensinogen ( AGT ) mRNA is endogenously bound by mir-122-5p and that rs699 A>G significantly decreases reporter mRNA in the functional mirSNP assay PASSPORT-seq. The AGT promoter variant rs5051 C>T is in linkage disequilibrium (LD) with rs699 A>G and increases AGT transcription. We hypothesized that the increased AGT by rs5051 C>T counterbalances AGT decrease by rs699 A>G, and when these variants occur independently, would translate to HTN-related phenotypes. The independent effect of each of these variants is understudied due to their LD, therefore, we used in silico, in vitro, in vivo , and retrospective clinical and biobank analyses to assess HTN and AGT expression phenotypes where rs699 A>G occurs independently from rs5051 C>T. In silico , rs699 A>G is predicted to increase mir-122-5p binding strength by 3%. Mir-eCLIP assay results show that rs699 is 40-45 nucleotides from the strongest microRNA binding site in the AGT mRNA. Unexpectedly, rs699 A>G increases AGT mRNA in a plasmid cDNA HepG2 expression model. GTEx and UK Biobank analyses demonstrate that liver AGT expression and HTN phenotypes were not different when rs699 A>G occurs independently from rs5051 C>T, allowing us to reject the original hypothesis. However, both GTEx and our in vitro experiments suggest rs699 A>G confers cell-type specific effects on AGT mRNA abundance. We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a 4-fold larger effect than in White participants. Further studies are warranted to determine if the altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394427,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"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":340350,"name":"Tyler Shugg","orcid":"0000-0002-5784-3565","position":1,"is_corresponding":false},{"id":1151804,"name":"Jacob Leighty","orcid":null,"position":2,"is_corresponding":false},{"id":465315,"name":"Matthew Martin","orcid":"0000-0002-3961-5809","position":3,"is_corresponding":false},{"id":943105,"name":"Rolf P. Kreutz","orcid":"0000-0002-2110-607X","position":4,"is_corresponding":false},{"id":307583,"name":"Michael T. Eadon","orcid":"0000-0003-3066-2876","position":5,"is_corresponding":false},{"id":94634,"name":"Dongbing Lai","orcid":"0000-0001-7803-580X","position":6,"is_corresponding":false},{"id":1151425,"name":"Tao Lu","orcid":"0000-0003-1783-6018","position":7,"is_corresponding":false},{"id":454682,"name":"Todd C. Skaar","orcid":"0000-0002-3849-374X","position":8,"is_corresponding":false},{"id":756046,"name":"Nicholas R. Powell","orcid":"0000-0003-4572-0733","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:19:14.590635Z","pmid":"37066278","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":[]}