达沙替尼药靶基因与结直肠癌因果关系及其免疫细胞中介作用的孟德尔随机化研究

Mendelian randomization analysis of the causal relationships between dasatinib target genes and colorectal cancer and the mediating role of immune cells

摘要:

背景与目的 结直肠癌（CRC）发病机制复杂，现有治疗对晚期转移性疾病效果有限。达沙替尼为多靶点酪氨酸激酶抑制剂，在多种实体瘤中表现出潜在抗肿瘤活性。本研究旨在基于基因遗传变异，评估达沙替尼相关靶基因与CRC的因果关系，并探索免疫细胞在其中的中介作用，以期为CRC的预防与靶向治疗提供遗传流行病学证据。方法 基于DrugBank确认达沙替尼相关靶基因，并从IEU OpenGWAS下载相应eQTL、CRC（ebi-a-GCST90018808）及731项免疫细胞性状的GWAS数据。采用双样本孟德尔随机化（MR）进行两步法中介分析：首先评估达沙替尼靶基因（作为暴露）与CRC的因果关系；其次评估靶基因与免疫细胞、免疫细胞与CRC之间的因果关系；最后计算中介效应占比。使用Wald比率、逆方差加权法（IVW）、MR-Egger、MR-PRESSO、Cochran's Q、I2及leave-one-out等方法检验异质性、多效性与稳健性。结果 MR结果表明，达沙替尼通过抑制ABL1与CRC风险显著降低（OR=0.511 0，95% CI=0.323 1~0.808 0，P=0.004 1）；抑制YES1亦与CRC风险降低相关（IVW OR=0.889 9，95% CI=0.811 6~0.975 8，P=0.013 1），且相关单核苷酸多态性未见显著异质性或水平多效性。进一步分析发现，达沙替尼抑制YES1显著降低IgD^-CD24^-AC的数量（OR=0.818 0，95% CI=0.678 2~0.986 7，P=0.035 7）；而该细胞亚群本身为CRC的危险因素（OR=1.105 7，95% CI=1.029 6~1.187 5，P=0.005 7）。中介分析显示，IgD^-CD24^-AC在ABL1→CRC与YES1→CRC路径中的中介占比分别为-9.89%与17.31%。结论 基于MR证据，达沙替尼通过抑制ABL1和YES1与CRC风险降低相关，且IgD^-CD24^-AC在YES1相关路径中部分中介了该保护效应。本研究为达沙替尼作为潜在CRC干预靶点提供了遗传-免疫学支持，但因数据源以欧洲人群为主且部分免疫表型文献有限，仍需实验学验证与跨族群重复研究以确认机制与临床意义。

Abstract:

Background and Aims Colorectal cancer (CRC) has a complex pathogenesis, and current treatments remain limited in efficacy for advanced metastatic disease. Dasatinib is a multi-target tyrosine kinase inhibitor that has shown potential antitumor activity in various solid tumors. This study aimed to evaluate the causal relationships between dasatinib-related target genes and CRC based on genetic variation, and to explore the mediating role of immune cells, thereby providing genetic epidemiological evidence for the prevention and targeted therapy of CRC.Methods Dasatinib-related target genes were identified through DrugBank, and the corresponding eQTLs, GWAS data for CRC (ebi-a-GCST90018808), and 731 immune-cell traits were obtained from the IEU OpenGWAS database. A two-sample Mendelian randomization (MR) framework with a two-step mediation approach was applied: first, to assess the causal relationship between dasatinib target genes (as exposures) and CRC; second, to evaluate the causal effects between target genes and immune cells, as well as between immune cells and CRC; and finally, to calculate the proportion of mediated effects. Wald ratio, inverse-variance weighted (IVW), MR-Egger, MR-PRESSO, Cochran's Q, I2, and leave-one-out analyses were used to examine heterogeneity, horizontal pleiotropy, and robustness.Results MR results showed that dasatinib-associated inhibition of ABL1 was significantly associated with a reduced risk of CRC (OR=0.511 0, 95% CI=0.323 1-0.808 0, P=0.004 1). Inhibition of YES1 was also associated with decreased CRC risk (IVW OR=0.889 9, 95% CI=0.811 6-0.975 8, P=0.013 1), with no evident heterogeneity or horizontal pleiotropy among the corresponding SNPs. Further analysis revealed that dasatinib-related inhibition of YES1 significantly reduced the levels of IgD^-CD24^-AC level (OR=0.818 0, 95% CI=0.678 2-0.986 7, P=0.035 7), and this immune cell subset itself was identified as a risk factor for CRC (OR=1.105 7, 95% CI=1.029 6-1.187 5, P=0.005 7). Mediation analysis indicated that IgD^-CD24^-AC accounted for -9.89% and 17.31% of the mediation effects in the ABL1→CRC and YES1→CRC pathways, respectively.Conclusion Genetic evidence from MR suggests dasatinib-target genes ABL1 and YES1 are causally linked to reduced CRC risk, with IgD^-CD24^-AC partially mediating the YES1-related protective effect. These findings point to immune-mediated mechanisms underlying dasatinib's potential influence on CRC risk; further experimental validation and replication across populations are warranted.