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

Chronic Diseases and translational Medicine 2024年第2期10卷 102-117页

作者： Nicholas R.Powell t.ler shugg Jacob Leighty Matthew Martin Rolf P.Kreutz Michael t.Eadon Dongbing Lai tao Lu todd C.Skaar Division of Clinical Pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Pharmacology and toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and Molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HtN)involves genetic variability in the renin-angiotensin system and influences antihypertensive *** 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 *** AGt promoter variant rs5051 C>t is in linkage disequilibrium(LD)with rs699 A>G and increases AGt *** 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 *** We used in silico,in vitro,in vivo,and retrospective models to test this *** 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 ***,rs699 A>G increases AGt mRNA in an AGt-plasmid-cDNA HepG2 expression ***-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>***,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 *** 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 *** studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>t or rs699 A>*** like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699

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