The AGPS regulatory variant rs113671272 confers esophageal squamous cell carcinoma susceptibility through allele-specific MEIS3 binding and NF-κB activation in Chinese populations.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) demonstrates pronounced ethnic disparities, being prevalent in Asian populations. However, the genetic mechanisms underlying this disparity remain poorly understood. This study aims to characterise the functional contribution of the regulatory variant rs113671272 in alkylglycerone phosphate synthase (AGPS) to ESCC susceptibility and prognosis in Chinese cohorts. METHODS: We conducted a two-phase genome-wide association study (GWAS) comprising 6172 participants to identify risk loci. Functional validation was conducted through Cleavage Under Targets & Tagmentation-quantitative PCR (CUT&Tag-qPCR) assay, Electrophoretic mobility shift assay (EMSA), and analyses of clinically annotated specimens with confirmed genotypes. In vitro and in vivo models, including RNA interference, and xenograft tumours, were employed to assess phenotypic effects. Transcriptomic profiling and Western blotting elucidated downstream pathways. Clinical correlations were evaluated in multi-ethnic cohorts. FINDINGS: AGPS 5'UTR regulatory variant rs113671272 was identified as a susceptibility locus for ESCC (OR = 1.15, P = 0.0004), with the A allele conferring poor survival. This variant localises to a putative active regulatory element marked by H3K27ac/H3K4me1/H3K4me3 and exhibits allele-specific binding to the transcription factor MEIS3. The co-expression of AGPS and myeloid ecotropic viral integration site 3 (MEIS3) was significantly associated with worse survival in Chinese, but not Caucasian patients with ESCC. MEIS3 knockdown significantly suppressed AGPS expression. AGPS knockdown inhibited ESCC cell proliferation, migration, and tumour growth, whereas its overexpression promoted oncogenic phenotypes via NF-κB activation. MEIS3 knockdown suppressed ESCC cell proliferation and migration, consistent with a pro-oncogenic role similar to that of AGPS. INTERPRETATION: Our results establish rs113671272 as a key ethnic-specific ESCC risk variant that operates through the MEIS3/AGPS/NF-κB regulatory axis. These findings provide mechanistic insights into population disparities in ESCC and highlight the potential of AGPS-targeted strategies for risk assessment and precision therapy in high-risk populations. FUNDING: National Natural Science Foundation of China U22A20326.