Long non-coding RNA gene polymorphisms and risk of recurrent pregnancy loss: a meta-analysis.

PURPOSE: Long non-coding RNAs (lncRNAs) are key regulators of transcriptional, epigenetic, and post-transcriptional processes involved in implantation, trophoblast function, and early placental development. Genetic polymorphisms within lncRNA loci may alter their expression or regulatory activity, potentially contributing to recurrent pregnancy loss (RPL). We aimed to evaluate the association between lncRNA gene polymorphisms and susceptibility to RPL. METHODS: A systematic review and meta-analysis were conducted according to PRISMA and MOOSE guidelines and prospectively registered in PROSPERO (CRD420261298804). A systematic search was performed in PubMed, Embase, Scopus, and Web of Science from database inception to January 2026, without language or date restrictions. Two reviewers independently screened studies, extracted data, and assessed risk of bias using ROBINS-E. Meta-analyses were performed using fixed- or random-effects models according to heterogeneity. Hardy-Weinberg equilibrium testing, sensitivity analyses, subgroup analyses by ancestry, and certainty of evidence assessment using the GRADE framework were conducted. RESULTS: Sixteen case-control studies involving 11,088 participants were included, comprising 5169 women with RPL and 6454 controls. Eight polymorphisms across four lncRNA genes were quantitatively synthesized. Significant associations with increased RPL susceptibility were observed for HOTAIR rs4759314 (AG vs AA: OR, 2.75 [95% CI, 2.04-3.71]; GG vs AA: OR, 2.16 [95% CI, 1.09-4.26]; G vs A: OR, 2.06 [95% CI, 1.48-2.88]) and HOTAIR rs920778 (CC vs TT: OR, 2.00 [95% CI, 1.28-3.11]; TC + CC vs TT: OR, 1.39 [95% CI, 1.09-1.76]; C vs T: OR, 1.38 [95% CI, 1.14-1.66]). A protective association was consistently identified for HOTTIP rs1859168 (CA vs AA: OR, 0.63 [95% CI, 0.45-0.89]; CC vs AA: OR, 0.33 [95% CI, 0.17-0.67]; C vs A: OR, 0.61 [95% CI, 0.45-0.82]). Sensitivity analysis further strengthened the evidence for HOTAIR rs1899663, with significant associations emerging for TT vs GG (OR, 2.59 [95% CI, 1.46-4.61]) and T vs G (OR, 1.41 [95% CI, 1.15-1.72]). Overall certainty of evidence for all pooled outcomes was rated as very low. CONCLUSION: This meta-analysis provides the first quantitative evidence that inherited variation within lncRNA loci may contribute to susceptibility to RPL. Variants in HOTAIR, particularly rs4759314 and rs920778, were associated with increased RPL risk, whereas HOTTIP rs1859168 showed a protective association. However, the certainty of evidence remains very low, and these findings should be interpreted cautiously until confirmed by large, well-designed, multi-ancestry studies with functional validation.