| 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 |
| DOI: | https://doi.org/10.1002/cdt3.103 |
| URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cdt3.103 |
Publication 9071
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Abstract
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. 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. </p>
Key points This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen ( AGT ) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver-mediated mechanisms. The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGT messenger RNA abundance in a cell-type-specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure. The association between rs699 A > G and rs5051 C > T and increased AGT expression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor-control receptors responsible for blood pressure-raising effects. Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G. </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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