Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension.

Autor: Powell NR; Division of Clinical Pharmacology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA., Shugg T; Division of Clinical Pharmacology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA., Leighty J; Division of Clinical Pharmacology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA., Martin M; Department of Pharmacology and Toxicology School of Medicine, Indiana University Indianapolis Indiana USA., Kreutz RP; Department of Cardiology School of Medicine, Krannert Institute of Cardiology, Indiana University Indianapolis Indiana USA., Eadon MT; Division of Nephrology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA.; Department of Medical and Molecular Genetics School of Medicine, Indiana University Indianapolis Indiana USA., Lai D; Department of Medical and Molecular Genetics School of Medicine, Indiana University Indianapolis Indiana USA., Lu T; Department of Pharmacology and Toxicology School of Medicine, Indiana University Indianapolis Indiana USA., Skaar TC; Division of Clinical Pharmacology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA.; Department of Medical and Molecular Genetics School of Medicine, Indiana University Indianapolis Indiana USA.
Jazyk: angličtina
Zdroj: Chronic diseases and translational medicine [Chronic Dis Transl Med] 2023 Dec 26; Vol. 10 (2), pp. 102-117. Date of Electronic Publication: 2023 Dec 26 (Print Publication: 2024).
DOI: 10.1002/cdt3.103
Abstrakt: Background: Hypertension (HTN) involves genetic variability in the renin-angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen ( AGT ) messenger RNA (mRNA) is endogenously bound by miR-122-5p and rs699 A > G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq. The AGT promoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGT transcription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C > T counterbalances AGT decreased by rs699 A > G, and when these variants occur independently, it translates to HTN-related phenotypes.
Methods: We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis.
Results: In silico, rs699 A > G is predicted to increase miR-122-5p binding affinity by 3%. Mir-eCLIP results show rs699 is 40-45 nucleotides from the strongest microRNA-binding site in the AGT mRNA. Unexpectedly, rs699 A > G increases AGT mRNA in an AGT -plasmid-cDNA HepG2 expression model. Genotype-Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell-type-specific effects on AGT mRNA abundance, and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A > G associations with HTN.
Conclusions: 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 fourfold larger effect than in White participants. Further studies are warranted to determine if 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.
Competing Interests: The authors declare no conflict of interest.
(© 2023 The Authors. Chronic Diseases and Translational Medicine published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)
Databáze: MEDLINE
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