Cellular senescence-related gene variants as risk factors for recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is characterized by two or more pregnancy losses. Despite its etiology encompassing known risk factors, over half of the cases remain idiopathic. In this sense, the search for molecular and cellular mechanisms that could be related to this condition is essential for explaining, at least in part, these cases. Cellular senescence (CS) is a state of cell cycle arrest that is present during reproduction and development; however, its impact on pregnancy remains unclear. Thus, our purpose was to evaluate the involvement of CS-related genes in the RPL context.

First, differential gene expression (DGE) of CDKN1A, CDKN2A, AKT1, EP300, TNF, and IFNG was assessed through a secondary analysis of publicly available datasets in the placenta and endometrium of RPL patients. Then, genetic variants (rs2395655, rs11515, rs1130233, rs20551, rs361525, and rs2430561, respectively) of these genes were evaluated in 107 women with RPL and 118 fertile controls. No difference in the expression of the genes assessed was found between the groups. On the other hand, the frequency of the CDKN1A allele A rs2395655 was more present in RPL patients than in fertile controls. In addition, a multiple comparison revealed two genotype combinations that were differently distributed between the groups (rs2395655 AG and rs11515 GG were more frequent in the RPL group; rs2395655 AG and rs11515 CG were more frequent in the controls), which might indicate them as associated with increased and decreased susceptibility factors, respectively, for RPL.

Although our data are preliminary, we hypothesize that CS may represent a fraction of RPL cases.