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

Objective: The aim of this study was to investigate the relationship between potential functional single-nucleotide polymorphisms (SNPs) of the angiotensin-converting enzyme 2 () gene and the pathogenesis of pre-eclampsia (PE) in Guangxi, China.

Materials And Methods: A case-control study was conducted involving 327 PE cases and 591 age-matched, normal, singleton pregnant women. Potential functional gene variants (rs2106809 A>G, rs6632677 G>C, and rs2074192 C>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).

Result: After adjusting for age and body mass index (BMI), unconditional logistic regression analysis showed that rs2106809 A>G was significantly associated with PE risk (AG . AA, OR = 1.43, 95% CI = 1.03-1.99, = 0.034; AG/GG . AA, OR = 1.45, 95% CI = 1.06-1.99, = 0.019), especially with severe PE (AG . AA, adjusted OR = 1.70, 95% CI = 1.10-2.61; AG/GG . 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) >23 kg/m (adjusted OR = 2.14, 95% CI = 1.32-3.45) and triglyceride (TG) >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 ( = 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>G causes a change in the reliability of classifications of two putative splice sites in the gene, potentially regulating the expression of functional genes (, , and ) in multiple tissues and cell lines ( 0.05).

Conclusion: The gene rs2106809 A>G variant is significantly associated with the risk of PE individual locus effects and/or complex gene-gene and gene-environment interactions. Regulating the expression of functional genes such as , , and may be the molecular mechanism by which rs2106809 increases an individual's susceptibility to PE.