GENETIC SUSCEPTIBILITY AND SINGLE-CELL TRANSCRIPTOMICS OF NON-CODING RNAS IN RECURRENT PREGNANCY LOSS
Abortion, Habitual; RNA, Untranslated; MicroRNAs; RNA, Long Noncoding; Killer Cells, Natural.
Recurrent pregnancy loss (RPL) constitutes a multifactorial reproductive condition whose etiology remains incompletely understood, with non-coding RNAs, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) being recognized as regulators of immune tolerance at the maternal-fetal interface. The objective was to investigate the role of these non-coding RNAs in the pathogenesis of RPL by integrating evidence from population genetic susceptibility with transcriptional data from decidual Natural Killer (dNK) cells. To this end, three studies were conducted: (1) a systematic review with meta- analysis of the association between polymorphisms in miRNA genes and susceptibility to RPL; (2) the first systematic review with meta-analysis on polymorphisms in lncRNA genes and RPL; and (3) a reanalysis of publicly available single-cell transcriptomic sequencing data from decidual tissue, including characterization of the lncRNA transcriptome in dNK cells, construction of competing endogenous RNA (ceRNA) networks, and pseudotemporal trajectory inference. In Study 1, 36 articles (14,230 participants) demonstrated a significant association between several miRNA polymorphisms (miR-10a, miR-27a, miR-125a, miR-323b, miR-449b, miR- 499b, and miR-604) and susceptibility to RPL, with effects modulated by ancestry. In Study 2, 16 studies (11,623 individuals) revealed a significant association of polymorphisms in HOTAIR, HOTTIP, and MALAT1 with the risk of RPL. In Study 3, single-cell analysis identified three functionally distinct dNK cell subpopulations and revealed widespread dysregulation of lncRNAs in patients with RPL, highlighting KLRK1-AS1, MIR155HG, and AP4B1-AS1 as hub lncRNAs of a pro-inflammatory regulatory axis composed of 37 effector genes, in addition to a progressive pseudotemporal trajectory from a basal tolerogenic state to a pro- inflammatory phenotype. It is concluded that non- coding RNAs, both through genetic variation and transcriptional dysregulation, participate in the immunological reprogramming of dNK cells in RPL, constituting potential biomarkers and therapeutic targets whose functional validation requires future studies.