To the best of our knowledge, this is the first study looking for an association between TNFR2 genetic polymorphism and PE. Interestingly, we found a significant correlation between the maternal genetic polymorphisms of TNFR2 rs1061622 (which is in strong linkage disequilibrium with the CA-repeat polymorphism) and PE. On the other hand, there was no link between the same fetal genetic variant and the disease. These results suggest that this TNFR2 variant allele or a polymorphism in proximity could be implicated in PE development. The cause and pathogenesis of PE are not completely understood, despite extensive research. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors contributing to the disease. One proposed mechanism is thought to be the consequence of impaired trophoblastic invasion of the maternal spiral arteries. This leads to placental hypoxia and the release of inflammatory factors that cause endothelial cell dysfunction. There is an increasing body of evidence that an exaggerated maternal systemic inflammatory response to pregnancy plays a central role in the pathogenesis of the disease. The excessive production of proinflammatory cytokines, chemokines and adhesion molecules may trigger a generalized endothelial dysfunction characteristic of the maternal syndrome of PE. Among the inflammatory molecules, the TNF pleiotropic inflammatory cytokine is assumed to play significant physiological and pathological roles in the placenta. It is generally accepted that TNF utilizes TNFR1 and TNFR2 to trigger distinct signal transduction pathways and to exert diverse biological functions in a context-dependant manner, including apoptosis, proliferation and differentiation. Under certain circumstances, TNFR2 may contribute to TNFR1 responses, particularly at low concentrations of TNF, consistent with the notion of ‘ligand passing’, in which TNFR2 captures TNF and passes it to TNFR1. Cooperation between the receptors may also be explained by the ligand-induced formation of TNF receptor heterocomplexes leading to cell death. It has been shown that in T cells, TNF-TNFR2 promotes proliferation. In oligodendrocytes, TNFR2 is critical in TNF-induced proliferation of progenitors and remyelination. In endothelial cells, TNFR2 induce in vitro, via Etk-VEGFR2 cross-talk, migration and tube formation, implying that this receptor may play a critical role in inflammatory angiogenesis, such as the ones occurring with ischemia, atherosclerosis or PE. In normal pregnancy, the TNFR2 protein is expressed in first-trimester cytotrophoblasts and syncytium with decreasing levels in these cell types toward the end of pregnancy. In the PE, the implication of TNFR2 is supported by studies showing that elevated levels of sTNFR2 are prior to overt PE and at the diagnostic stage. Moreover, elevated serum levels of TNF, as well as increased mRNA/protein expression of TNF/TNFR were noticed in the leukocytes and placenta of PE women. Functional analyses from mice genetically deficient of TNFR demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis. The TNFR signaling analysis indicated that TNFR1 induce decreased arteriogenesis, angiogenesis, and associated endothelial cell proliferation, neovascularization, and vessel maturation, whereas TNFR2 induce an increase.[31-34] The TNFR2 gene is located on chromosome 1p36.2 and is organized in 10 exons and nine introns. In addition to non-coding SNP in exons 4, 9, and 10, a further SNP (T/G) was described in exon 6 at nucleotide 676 of the TNFR2 mRNA resulting in an amino acid exchange in the fourth extracellular cysteine-rich domain (CRD4) from methionine (TNFR2 196MET) to arginine (TNFR2 196ARG) at position 196. Exon 6 encodes a small portion of the transmembrane region and contains the position of the proteolytic cleavage site that produces the soluble form of TNFR2. Receptor shedding provides a mechanism for downregulating a cell surface receptor and a means of releasing a biologically active, soluble receptor, which may act as a receptor-antagonist by capturing free-circulating ligand. Investigations of the functional impact of a single nucleotide polymorphism in exon 6 of the TNFR2 gene demonstrated that the TNFR2 196ARG risk variant has a significantly lower capability to induce direct NF-kB signaled via TNFR2 in human epithelial cells. The diminished capability of the mutated TNFR2 196ARG to induce NF-kB activation is paralleled by a diminished induction of NF-kB-dependent target genes conveying either anti-apoptotic or pro-inflammatory functions, such as cIAP1, cIAP2, TRAF1, IL-6, and IL-8. Moreover, T676G polymorphism in TNFR2 is associated with levels of sTNFR released from peripheral blood T cells, and with circulating levels of sTNFR in patients with rheumatoid arthritis; however physical binding parameters appear to be not influenced by the substitution.[14, 15] The functional impact of this SNP remains to be demonstrated in endothelial cells; however, if we hypothesized that the effect of this SNP, described in epithelial cells, could be similar in endothelial and bone marrow-derived cells, the TNFR2 (196R) variant could reduce signaling receptors leading to reduced survival, migration and tube formation and contribute to arteriogenesis and angiogenesis in local placenta. Subsequently, this polymorphism could lead to a poor placentation and to the endothelial dysfunction described in PE. Thus, this polymorphism could contribute to explaining the risk of PE, at least for Tunisian women. Future studies among different ethnic populations are needed to determine whether our results can be extended to other ethnic groups.