The angiotensin-I-converting enzyme insertion/deletion in polymorphic element codes for an AluYa5 RNA that downregulates gene expression

Abstract

Angiotensin-I-converting enzyme (ACE) is involved in the synthesis and degradation of important bioactive peptides. The ACE gene has a 287-bp insertion/deletion polymorphism that controls ACE expression through a mechanism that remains elusive. In this study, we found that the 287-bp polymorphic element of the ACE gene, a member of the AluYa5 sub-family of Alu elements, codes for an RNA molecule that controls the levels of ACE mRNA. Transient transfection of a plasmid containing a CMV promoter upstream of the ACE polymorphic element resulted in significant expression of an AluYa5 RNA and reduced ACE mRNA expression as well as ACE enzymatic activity in AD 293 cells. The AluYa5 element also independently reduced the expression of other genes, regardless of whether these genes harbored Alu elements within their genomic context. Interestingly, the CMV promoter was not required for the expression of the AluYa5 element in AD 293 cells. The 287-bp sequence was sufficient to produce AluYa5 RNA and led to a significant reduction in ACE gene expression. Moreover, the removal of an 11-bp fragment of the 3' end of the ACE polymorphic sequence, which is specific to this particular AluYa5 element, did not prevent this element from being expressed but did affect its ability to target ACE expression. Thus, the expression of the AluYa5 polymorphic element within the ACE gene could explain why patients carrying the ACE insertion polymorphism have reduced risk of developing several chronic diseases.

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: a systematic review and meta-analysis

“…The majority of studies included in the present data synthesis analyzed genetic variant rs1799752 located within ACE1 . Even though this polymorphism is intronic, it was shown that the presence of Alu insertion (I allele) correlates with the lower expression of ACE1, possibly via regulation of the transcription rate (Mafra et al, 2018[ 29 ]; Mariner et al, 2008[ 31 ]; Rigat et al, 1990[ 44 ]). The protective effect of the same allelic variant against severe COVID-19 was shown in Spanish and Turkish COVID-19 patients (Aladag et al, 2021[ 4 ]; Gómez et al, 2020[ 20 ]).…”

Angiotensin–Converting Enzyme (ACE) 1 Gene Polymorphism and Phenotypic Expression of COVID-19 Symptoms

“…Despite the fact that the Alu is an intron insertion, it can affect gene expression through several mechanisms, including both genetic and epigenetic pathways [60]. At the molecular level, it has also been reported that the presence of the Alu element within intron 16 probably affects the promoter activity of ACE1, which acts as a transacting repressor for RNA polymerase II activity [61,62]. Strikingly, ACE1 levels in the blood are determined by this I/D polymorphism [63].…”

“…Elevated STAT3 also activates PD-L1 in endothelial cells, leading to T-cell lymphopenia [70]. FXIIIB polymorphism AluYa5 insertion has been reported to confer a risk of coronary atherosclerosis [61]. Furthermore, intra-and extracellular FXIIIs are indicated to support the immobilization and killing of bacteria as well as phagocytosis by macrophages, strongly suggesting that FXIII may also function in innate immunity [71].…”

Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection

“…Some polymorphisms in ACE gene are reported to influence the efficacy of these inhibitors among them is the homozygous ACE haplotypes which lead to faster response to ramipril [61]. The expression and function of the ACE itself are affected by its polymorphisms which are associated with susceptibility to different diseases such as hypertension and diabetes mellitus [93]. Notably, polymorphisms in both ACE and ACE2 are important in the regulation of the ACE2 expression [94,95].…”