尽管全基因组关联研究 (GWAS) 已识别出 200 多个与结直肠癌 (CRC) 相关的风险位点，但这些位点内的致病基因或风险变异及其生物学功能仍未完全揭示。最近，具有先导 SNP rs1800469 的基因组位点 19q13.2 被确定为亚洲人群中关键的 CRC 风险位点。然而，该区域的功能机制尚未完全阐明。在这里，我们采用基于 RNA 干扰的芯片方法来筛选 CRC 风险位点 19q13.2 中细胞增殖必需的基因。值得注意的是，我们发现 RPS19 在已识别的基因中表现出最显着的作用，并作为促进 CRC 细胞增殖的关键癌基因。随后，结合综合精细绘图分析和由 6027 例病例和 6099 名对照组成的大规模人群研究，我们优先考虑 rs1025497 作为 CRC 风险的潜在因果候选者，证明 rs1025497[A] 等位基因显着降低了 CRC 风险（或0.70，95%置信区间 = 0.56-0.83，P = 1.12 × 10-6），这在英国生物银行队列中得到了进一步验证，该队列包括5,313例病例和21,252名对照。从机制上讲，我们通过实验阐明了变体 rs1025497 可能作为等位基因特异性沉默子，抑制转录抑制因子 HBP1 介导的癌基因 RPS19 的表达水平。总而言之，我们的研究揭示了 RPS19 在 CRC 发病机制中的重要作用，并描述了其由 rs1025497 介导的远端调节机制，增进了我们对 CRC 病因学的理解，并为人类癌症的个性化医疗提供了新的见解。© 2024。作者（ s)，获得 Springer-Verlag GmbH 德国（施普林格自然的一部分）的独家许可。

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.