Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
School of Medicine, Fudan University, Shanghai, 200240, China.
J Transl Med. 2024 Jun 10;22(1):557. doi: 10.1186/s12967-024-05363-9.
Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment.
We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes' expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR.
Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies.
By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.
解析血浆蛋白在胰腺癌（PC）易感性中的作用有助于发现新的诊断和治疗靶点。
我们通过利用来自多个中心的顺式-pQTL 进行系统的蛋白质组全孟德尔随机化（MR）分析，研究了遗传决定的血浆蛋白水平与 PC 之间的关系。严格的敏感性分析、共定位、反向 MR、使用不同工具变量选择和其他数据集的复制以及随后的荟萃分析用于证实显著发现的稳健性。然后研究了相应蛋白编码基因表达的因果效应及其在单细胞类型中的表达模式。富集分析、蛋白质间相互作用和因果关系、敲除小鼠模型以及用已建立的 PC 风险因素进行的中介分析用于指示发病途径。最后根据药物可开发性和表型全 MR 预测的潜在副作用对这些候选靶点进行了优先级排序。
在探索性阶段确定了 21 种与 PC 相关的循环蛋白，没有水平多效性或反向因果关系的证据。其中 11 种在整合外部验证的荟萃分析中得到了证实。在转录水平上的因果关系在中性粒细胞弹性蛋白酶、羟酰基谷胱甘肽水解酶、脂肪酶 N、蛋白二硫键异构酶 A5、木糖苷木糖基转移酶 1 中得到了重复。碳水化合物磺基转移酶 11 和组织血型 ABO 系统转移酶表现出高支持遗传共定位证据，并被发现通过分别调节体重指数和 2 型糖尿病部分影响 PC 癌变。八种候选靶点已经建立了批准的药物，这些药物可能被重新用于 PC 治疗。表型全研究揭示了与 51 种非 PC 特征相关的 12 种蛋白质，而对蛋白二硫键异构酶 A5 和胱抑素-D 的干扰会增加其他恶性肿瘤的风险。
通过采用综合方法，本研究表明遗传易感性将 21 种循环蛋白与 PC 风险联系起来。我们的研究结果为 PC 的病因学提供了新的认识，并强调了潜在的靶点作为 PC 早期诊断和治疗策略的未来努力的重点。
