AUTHOR=Huang Gongchen , Wang Yukun , Qin Linyuan , Huang Bo , Yu Xiangyuan 

TITLE=Association and functional analysis of angiotensin-converting enzyme 2 genetic variants with the pathogenesis of pre-eclampsia

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.926512

DOI=10.3389/fendo.2022.926512

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>The aim of this study was to investigate the relationship between potential functional single-nucleotide polymorphisms (SNPs) of the angiotensin-converting enzyme 2 (<italic>ACE2</italic>) gene and the pathogenesis of pre-eclampsia (PE) in Guangxi, China.</p></sec><sec><title>Materials and methods</title><p>A case–control study was conducted involving 327 PE cases and 591 age-matched, normal, singleton pregnant women. Potential functional <italic>ACE2</italic> gene variants (rs2106809 A&gt;G, rs6632677 G&gt;C, and rs2074192 C&gt;T) were selected and genotyped using kompetitive allele-specific PCR. The strength of the associations between the studied genetic variants and the risk of PE were evaluated using odds ratios (ORs) and corresponding 95% confidence intervals (CIs).</p></sec><sec><title>Result</title><p>After adjusting for age and body mass index (BMI), unconditional logistic regression analysis showed that rs2106809 A&gt;G was significantly associated with PE risk (AG <italic>vs</italic>. AA, OR = 1.43, 95% CI = 1.03–1.99, <italic>p</italic> = 0.034; AG/GG <italic>vs</italic>. AA, OR = 1.45, 95% CI = 1.06–1.99, <italic>p</italic> = 0.019), especially with severe PE (AG <italic>vs</italic>. AA, adjusted OR = 1.70, 95% CI = 1.10–2.61; AG/GG <italic>vs</italic>. AA, adjusted OR = 1.71, 95% CI = 1.14–2.57). Further stratified analysis showed that rs2106809 was even more pronounced in subjects in the pre-pregnancy BMI (pre-BMI) &gt;23 kg/m<sup>2</sup> (adjusted OR = 2.14, 95% CI = 1.32–3.45) and triglyceride (TG) &gt;2.84 mmol/L subgroups (adjusted OR = 1.81, 95% CI = 1.09–3.01) under the dominant genetic model. We also found that rs2106809 interacted with pre-BMI (<italic>p</italic><sub>interaction</sub> = 0.040), thereby affecting an individual’s genetic susceptibility to PE. Multiple dimension reduction analysis demonstrated that rs2106809 made the best one-locus model, and the three-locus model was the best interaction model for predicting PE risk. Functional analysis suggested that rs2106809 A&gt;G causes a change in the reliability of classifications of two putative splice sites in the <italic>ACE2</italic> gene, potentially regulating the expression of functional genes (<italic>PIR</italic>, <italic>ACE2</italic>, and <italic>CLTRN</italic>) in multiple tissues and cell lines (<italic>p&lt;</italic> 0.05).</p></sec><sec><title>Conclusion</title><p>The <italic>ACE2</italic> gene rs2106809 A&gt;G variant is significantly associated with the risk of PE <italic>via</italic> individual locus effects and/or complex gene–gene and gene–environment interactions. Regulating the expression of functional genes such as <italic>PIR</italic>, <italic>ACE2</italic>, and <italic>CLTRN</italic> may be the molecular mechanism by which rs2106809 increases an individual’s susceptibility to PE.</p></sec>