Long noncoding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci (eQTL) analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies (GWASs) and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, including SNHG7 (OR = 1.16, 95%CI: 1.09 - 1.23), NRAV (OR = 1.11, 95%CI: 1.05 - 1.17), LINC01082 (OR = 1.16, 95%CI: 1.08 - 1.22) and FENDRR (OR = 1.16, 95%CI: 1.07 - 1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in upregulation of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development.

中文翻译：

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12q24.31 风险位点中的长非编码 RNA NRAV 通过葡萄糖代谢重编程驱动胃癌的发生。

长非编码 RNA (lncRNA) 是介导癌症风险的重要候选者。在这里，我们的目的是识别单核苷酸多态性（SNP）诱导的lncRNA的风险，并研究它们在胃癌（GC）发展中的作用。通过整合GC组织中lncRNA的差异表达分析和正常胃组织和GC组织中的表达数量性状位点（eQTL）分析，以及基于GC全基因组关联研究（GWAS）和独立验证研究的遗传关联分析，我们确定了四个与 GC 风险一致相关的 lncRNA 相关 SNP，包括 SNHG7 (OR = 1.16, 95%CI: 1.09 - 1.23)、NRAV (OR = 1.11, 95%CI: 1.05 - 1.17)、LINC01082 (OR = 1.16) ，95%CI：1.08 - 1.22）和 FENDRR（OR = 1.16，95%CI：1.07 - 1.25）。我们进一步发现 12q24.31 处的功能性 SNP rs6489786 增加远端增强子处 MEOX1 或 MEOX2 的结合，并导致 NRAV 上调。功能测定表明，NRAV 加速 GC 细胞增殖，同时抑制 GC 细胞凋亡。从机制上讲，NRAV 通过电子传递链降低关键亚基基因的表达，从而驱动葡萄糖代谢从有氧呼吸重编程为糖酵解。这些发现表明，调节 lncRNA 表达是风险相关变异促进 GC 发展的关键机制。