Double hit of NEMO gene in preeclampsia

Abstract

The precise etiology of preeclampsia is unknown. Family studies indicate that both genetic and environmental factors influence its development. One of these factors is NFkB, whose activation depends on NEMO (NFkB essential modulator. This is the first study to investigate the association between the existence of single nucleotide variant of the NEMO gene and the appearance of preeclampsia. A total of 151 women (72 preeclamptic women and 79 controls) and their children were examined. Sanger sequencing was performed to identify variants in the NEMO gene in the preeclamptic mothers. The maternal identified variants were then sought in the studied groups of children, and in the maternal and child controls, using RFLP-PCR. Real-time RT-PCR was performed to assess NEMO gene expression in maternal blood, umbilical cord blood and placentas. The sequencing process indicated the existence of two different variants in the 3'UTR region of the NEMO gene of preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T). The simultaneous occurrence of the TT genotype in the mother and the TT genotype in the daughter or a T allele in the son increased the risk of preeclampsia development 2.59 fold. Additionally, we found that the configuration of maternal/fetal genotypes (maternal TT/ daughter TT or maternal TT/son T) of IKBKG:c.*402C/T variant is associated with the level of NEMO gene expression. Our results showed that, the simultaneous occurrence of the maternal TT genotype (IKBKG:c.*402C>T variants) and TT genotype in the daughter or T allele in the son correlates with the level of NEMO gene expression and increases the risk of preeclampsia development. Our observations may offer a new insight into the genetic etiology and pathogenesis of preeclampsia.

Questionnaire survey on association between preeclampsia and incontinentia pigmenti

“…Schematic representation of relationship between preeclampsia, incontinentia pigmenti and NEMO/IKBKG gene. : * : This article; Ref …”

“…Multiple mechanisms of pathogenicity of PE have been proposed, nevertheless, the exaggeration of systemic inflammation and endothelial dysfunction are still considered to be the most possible mechanisms . Studies have shown that PE is associated with an improper immune response and milieu of alternatively activated immune cells and cytokines . Placental ischemia, resulting from the insufficient trophoblast invasion seen in PE, has been shown to produce an imbalance in immune function that leads to chronic inflammation and manifests similarly to an autoimmune disease .…”

“…As many autoimmune diseases and PE have genetic variants associated with NF‐κB, it is likely that genetically mediated variability in this pathway is central to disease development. In addition, as the variants associated with each disorder are different, variation in the NF‐κB pathway may result in changes in signaling that are specific to each disease …”

“…18,19 Studies have shown that PE is associated with an improper immune response and milieu of alternatively activated immune cells and cytokines. 6,7,19,20 Over all Placental ischemia, resulting from the insufficient trophoblast invasion seen in PE, has been shown to produce an imbalance in immune function that leads to chronic inflammation and manifests similarly to an autoimmune disease. 21 In 2008, Xia et al 22 reported the first animal-based evidence that PE may be a pregnancy-induced autoimmune disease.…”

“…4 Family studies indicate that both genetic and environmental factors influence its development; genetic factors have a greater influence. 5 Recently, Sakowicz et al 6,7 first reported an association between single nucleotide variant in NEMO/ IKBKG gene and the elevated risk of PE development. The simultaneous occurrence of a TT genotype in the mother and daughter, or a T allele in her son, was associated with significant increase in the risk of hypertension and proteinuria appearance during gestation.…”