TNF-α G308A Gene Polymorphism Has an Impact on Renal Function, Microvascular Permeability, Organ Involvement and Severity of Preeclampsia

Abstract

Background/Aims: Preeclampsia (PE) is a life-threatening complication of pregnancy that is associated with a high rate of maternal and perinatal morbidity and/or mortality worldwide. If untreated, it can progress to eclampsia, which can result in the death of the mother, the fetus or both. The etiology of PE is still uncertain; however, recently the role of the immune system has gained in importance. The role of tumor necrosis factor-α (TNF-α), a cytokine involved in inflammation processes, has been widely investigated in obstetric disorders. The aims of the present study were to investigate the effect of TNF-α gene G308A (rs1800629) polymorphism on disease risk, renal function, microvascular permeability, endothelial cell dysfunction and organ involvement in women with PE. Methods: Initially, 102 3rd-trimester pregnant women (preeclamptic cases and healthy controls) with singleton pregnancy were invited for participation, of which 76 were genotyped for TNF-α G308A polymorphism and evaluated for plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), fibronectin and TNF-α, which were tested for correlations with the profile of PE. The odds ratio (OR) and 95% confidence intervals obtained from unconditional logistic regression were used to test the association between the TNF-α polymorphism and PE risk. For continuous variables, we applied Student's t test and, for categorical variables, the Pearson χ² or Fisher's exact test. The two-way ANOVA test with Bonferroni correction was used in multivariate analyses. Results: The A allele was more frequent in cases than controls (22.4 vs. 13.2%), which increased disease risk (OR = 2.73). Maternal serum levels of TNF-α, sVCAM-1 and fibronectin were significantly increased in cases (855.8 ± 385.1 pg/ml, 1,243 ± 671 ng/ml, 0.308 ± 0.231 g/l, respectively) compared to controls (301.1 ± 156.1 pg/ml, 651 ± 250 ng/ml, 0.218 ± 0.101 g/l, respectively; p < 0.0001, p < 0.0001 and p = 0.031, respectively), and these levels showed an increasing trend with the mutant allele genotype. Moderate and severe proteinuria was higher in rs1800629 allele A subjects compared to G/G carriers (53.8 vs. 14.3% (p < 0.05) and 13.0 vs. 4.7% (p < 0.01), respectively). The adverse effect of rs1800629 allele A on renal function was confirmed by increased plasma creatine levels, urinary protein excretion and lower tubular resorption rate in preeclamptic patients. Moreover, rs1800629 allele A preeclamptic carriers showed higher serum levels of fibronectin and sVCAM-1 compared to G/G homozygotes. Conclusion: This study reveals a possible association between clinical and laboratory manifestations of PE and the TNF-α gene G308A (rs1800629) polymorphism.

A Case-Control Study Indicates that no Association Exists Between Polymorphisms of IL-33 and IL-1RL1 and Preeclampsia

“…As PE is a polygenetic hereditary disease and previous studies have been indicated that many cytokine genes are associated with susceptibility to it such as VEGF [35,36], NLRP1 [37], IL-1 [15,16], TNF-α [17,18], IFN-γ [19] and so on. Therefore in the present study we investigated whether IL-33 rs3939286 and IL-1RL1 rs13015714 play pivotal roles in the development of PE.…”

“…PE is a complex polygenetic hereditary disease involving both genetic and environmental factors [14] and previous studies have identified many candidate genes associated with susceptibility to it, such as IL-1 [15,16], TNF-α [17,18], IFN-γ [19] and so on. We therefore hypothesize that IL-33 and IL-1RL1 might play critical roles in pathophysiology of PE.…”

Role of Toll-Like Receptor 3 Gene Polymorphisms in Preeclampsia

“…Although various candidate genes, such as IFN-γ, IL-1 and TNF-α [14][15][16], have been shown to have associations with PE, the exact genes involved remain controversial. As important functional variants, TLR3 rs3775296 (in the 5′-UTR) and rs3775291 (in exon 4) polymorphisms affect the expression and cell surface localization of TLR3 and, thereby, influence NF-κB cascade induction [17].…”

Complement Split Products C3a/C5a and Receptors: Are They Regulated by Circulating Angiotensin II Type 1 Receptor Autoantibody in Severe Preeclampsia?

“…The complement pathway is involved in the production of inflammatory cytokines, chemokines and angiogenic factors [5,6,7,8,9] that are associated with adverse pregnancy outcomes. Complement is a system comprised of over 35 proteins and 3 main activation pathways.…”