| Title: | Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension |
| Journal: | Chronic Diseases and Translational Medicine |
| Published: | 26 Dec 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38872760/ |
| DOI: | https://doi.org/10.1002/cdt3.103 |
| URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cdt3.103 |
| Citations: | 2 (2 in last 2 years) as of 8 Aug 2024 |
Publication 9071
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Abstract
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.</p>
Methods: We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis.</p>
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.</p>
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.</p>
9 Authors
- Nicholas R. Powell
- Tyler Shugg
- Jacob Leighty
- Matthew Martin
- Rolf P. Kreutz
- Michael T. Eadon
- Dongbing Lai
- Tao Lu
- Todd C. Skaar
1 Application
| Application ID | Title |
|---|---|
| 86441 | Investigating genetic variants identified from drug toxicity cases |
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