蛋白质组是治疗靶点的主要来源。我们进行了一项蛋白质组全面门迪利亚随机试验研究，以鉴定结直肠癌（CRC）的候选蛋白标志物和治疗靶点。通过七项已发表的全基因组关联研究（GWAS）提取的蛋白定量性状位点（pQTLs），对4853个循环蛋白标志物提取了总结水平数据。结直肠癌的遗传关联来自大规模GWAS荟萃分析（16,871个病例和26,328个对照），FinnGen队列（4957个病例和304,197个对照），和UK Biobank（9276个病例和477,069个对照）。顺序执行共定位分析和总结数据MR（SMR）分析，以验证候选蛋白的因果作用。进一步进行单一细胞类型表达分析，蛋白质相互作用（PPI）和可药性评估，以检测具有富集表达的特定细胞类型并优先选择潜在的治疗靶点。综合而言, 遗传预测的13种蛋白质水平与CRC风险相关。其中两种蛋白质（GREM1，CHRDL2）的升高水平与CRC风险增加相关，另外11种蛋白质降低水平与CRC风险增加呈正相关，其中有4个蛋白质（GREM1, CLSTN3, CSF2RA, CD86）具备最有说服力的证据。这些编码蛋白质的基因主要在结肠肿瘤组织中的组织干细胞、上皮细胞和单核细胞中表达。在骨髓破骨细胞分化和肿瘤发生途径中鉴定出两个蛋白质互作对（GREM1和CHRDL2；MMP2和TIMP2)。在自身免疫疾病和其他癌症的药物开发中已针对四种蛋白质（POLR2F，CSF2RA，CD86，MMP2），具备作为CRC治疗靶点再利用的潜力。该研究鉴定了几个与CRC风险相关的蛋白标志物，并为开发CRC筛查标志物和治疗药物提供了新的见解。© 2023. BioMed Central Ltd., Springer Nature的一部分。

The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC).Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets.Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC.This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.© 2023. BioMed Central Ltd., part of Springer Nature.