Background: The long non-coding RNA HOTAIR has been implicated in tumor initiation and progression, and multiple case–control studies have explored whether common HOTAIR single-nucleotide polymorphisms influence susceptibility to gastrointestinal (digestive system) malignancies. However, published findings remain inconsistent across populations and cancer types. Methods: We systematically searched PubMed, Embase, China National Knowledge Infrastructure, and Wanfang for eligible case-control studies evaluating associations between HOTAIR polymorphisms and digestive system cancer risk. Pooled odds ratios with 95% confidence intervals were calculated to estimate genetic effects. Between-study heterogeneity guided the use of fixed- or random-effects models. Prespecified subgroup analyses, sensitivity analyses, and publication-bias assessments were performed. Results: A total of 25 studies comprising 12,521 cases and 14,610 controls were included. Overall evidence supported an association between digestive system cancer susceptibility and rs920778 (C>T) as well as rs4759314 (A>G), with signals persisting in several subgroup analyses. In contrast, rs7958904 (G>C) showed a risk-reducing pattern in the overall analysis and in colorectal cancer–focused comparisons. No convincing association was observed for rs1899663 (G>T) or rs874945 (G>A). Evidence for less frequently investigated loci (e.g., rs12826786 and rs17720428) was limited and warrants further validation. Conclusions: Current pooled data suggest that selected HOTAIR variants – particularly rs920778 and rs4759314 – may contribute to inherited susceptibility to digestive system cancers, whereas rs1899663 and rs874945 appear unrelated in available datasets. Larger, well-designed studies across diverse ancestries and cancer sites are needed to confirm these findings and clarify potential gene–environment interactions.
Xie et al. (Fri,) studied this question.