Powell Nicholas R, Shugg Tyler, Leighty Jacob, Martin Matthew, Kreutz Rolf P, Eadon Michael T, Lai Dongbing, Lu Tao, Skaar Todd C
Division of Clinical Pharmacology, Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA.
Department of Pharmacology and Toxicology School of Medicine, Indiana University Indianapolis Indiana USA.
Chronic Dis Transl Med. 2023 Dec 26;10(2):102-117. doi: 10.1002/cdt3.103. eCollection 2024 Jun.
Hypertension (HTN) involves genetic variability in the renin-angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen () 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 promoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases transcription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased by rs5051 C > T counterbalances decreased by rs699 A > G, and when these variants occur independently, it translates to HTN-related phenotypes.
We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis.
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 mRNA. Unexpectedly, rs699 A > G increases mRNA in an -plasmid-cDNA HepG2 expression model. Genotype-Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver 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 mRNA abundance, and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A > G associations with HTN.
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.
高血压（HTN）涉及肾素 - 血管紧张素系统的基因变异性，并影响降压反应。我们之前报道过血管紧张素原（）信使核糖核酸（mRNA）内源性地与miR - 122 - 5p结合，并且在微小RNA功能测定PASSPORT - seq中，rs699 A＞G会降低报告基因mRNA。启动子变体rs5051 C＞T与rs699 A＞G处于连锁不平衡（LD）状态，且会增加转录。由于这些变体的连锁不平衡，它们的独立作用尚未得到充分研究，因此我们旨在检验以下假设：rs5051 C＞T导致的增加会抵消rs699 A＞G导致的减少，并且当这些变体独立出现时，会转化为与高血压相关的表型。
我们使用了计算机模拟、体外、体内和回顾性模型来检验这一假设。
在计算机模拟中，rs699 A＞G预计会使miR - 122 - 5p结合亲和力提高3%。Mir - eCLIP结果显示，rs699距离血管紧张素原mRNA中最强的微小RNA结合位点40 - 45个核苷酸。出乎意料的是，在血管紧张素原质粒 - cDNA HepG2表达模型中，rs699 A＞G会增加血管紧张素原mRNA。基因型 - 组织表达（GTEx）和英国生物银行分析表明，当rs699 A＞G独立于rs5051 C＞T出现时，肝脏血管紧张素原表达和高血压表型并无差异。然而，GTEx和体外实验表明，rs699 A＞G对血管紧张素原mRNA丰度具有细胞类型特异性影响，并表明旁分泌性肾素 - 血管紧张素系统扰动可能介导rs699 A＞G与高血压的关联。
我们发现，在英国生物银行的黑人参与者中，rs5051 C＞T和rs699 A＞G与收缩压显著相关，其影响是白人参与者的四倍。有必要进一步研究黑人个体降压反应改变是否可能归因于rs5051 C＞T或rs699 A＞G。这样的研究将有助于临床医生不再仅仅将种族作为基因型的替代指标。
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