Contribution of angiotensinogen M235T and T174M gene variants and haplotypes to preeclampsia and its severity in (North African) Tunisians

Abstract

Background:Preeclampsia (PE) is a pregnancy-associated hypertensive disorder and a leading cause of maternal and neonatal morbidity and mortality. While its pathogenesis remains ill defined, several candidate genes for PE have been identified, but results remain inconclusive. We investigated the association of the angiotensinogen (AGT) gene variants M235T and T174M with PE, and we analyzed the contribution of both variants to the severity of PE.Methods:This case-control study enrolled 550 Tunisian pregnant women: 272 with PE, of whom 147 presented with mild, and 125 with severe PE, along with 278 unrelated age- and ethnically matched control women. AGT genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism.Results:Significantly higher M235T minor allele frequency (MAF) was associated with increased risk of PE (p < 0.001). Decreased frequency of heterozygous T174M genotype carriers were found in control women (p = 0.015), suggesting a protective effect of this genotype (odds ratio (95% confidence interval) = 0.51 (0.29–0.89)). Two-locus haplotype analysis demonstrated MM and TT haplotypes to be negatively and positively associated with PE, respectively. MAF of M253T, but not T174M, was higher in the severe PE group, and carrying M235T or T174M minor allele was associated with increased body mass index (p < 0.001) among unselected PE women.Conclusions:AGT M235T and T174M variants contribute to an increased risk of developing PE, and for M235T to PE severity.

Three polymorphisms of renin-angiotensin system and preeclampsia risk

“…1 show the main characteristics of the included studies and the study selection flow chart, respectively. A total of forty studies were finally included in our metaanalysis [1,5,[7][8][9], among which thirty-four studies Table 2 summarizes the overall and subgroup results regarding the associations between the ACE I/D, AGT T704C, and AT1R A1166C polymorphisms and PE risk. Extensive significant associations were observed for ACE I/D and AGT T704C polymorphisms; however, for the AT1R A1166C polymorphism, no association was detected.…”

“…In pregnant women with PE, downregulated renin-angiotensin system (RAS) activity is observed, resulting in increased vascular responsiveness to angiotensin II [4]. The increased plasm levels of angiotensin (AGT) and angiotensin converting enzyme (ACE) in PE subjects lead to the augmentation of angiotensin II [5,54]; moreover, the pathophysiological effects of angiotensin II are enhanced by the upregulation of angiotensin II type 1 receptor (AT1R) [9], causing the dysregulation of blood pressure. Gene polymorphisms were reported to be associated with the abnormal expression of mRNA and protein [55,56].…”

“…The inclusion criteria for studies were as follows: (1) casecontrol studies discussing the relationship between ACE I/D, AGT T704C, AT1R A1166C polymorphisms, and preeclampsia risk; (2) the diagnostic criteria for preeclampsia were defined as gestational hypertension, assessed as SBP > 140 mmHg, DBP > 90 mmHg, and/or rise in SBP > 30 mmHg or DBP > 15 mmHg on at least two occasions 6 h apart, following 20 weeks of gestation, with marked proteinuria (> 300 mg/24 h), or > 2+ proteinuria as tested by the dipstick method [5,11,12]; (3) the frequencies of the related polymorphisms in patients and controls could be retrieved to calculate odds ratio with 95% confidence intervals and to assess Hardy-Weinberg equilibrium. The exclusion criteria were (1) reviews or case reports or animal studies; (2) studies without reporting detailed genotype data; and (3) duplicated studies.…”

“…During normal pregnancy, the upregulation of renin and aldosterone triggered by the stimulation of the RAAS system maintains the balance of blood volume and blood pressure [4]; however, for PE subjects, depression of the RAAS system with increased vascular resistance was observed, suggesting its crucial role in the pathogenesis of PE [5]. Angiotensin (AGT), angiotensin converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) are the three pivotal nodes in the RAAS system.…”

Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia

“…Angiotensin converting enzyme (ACE) along with AGT receptor 1 (AGTR1) were also found to have a role in the pathogenesis of the preeclampsia. Another candidate gene that link preeclampsia to the risk of hypertension is the T allele (C677T) of the methylenetetrahydrofolate reductase (MTHFR) gene [19][20][21][22][23].…”