Carboxypeptidase M: unveiling a new therapeutic target for osteonecrosis based on eQTL Database and Finnish Genetic Big Data

doi:10.12307/2026.037

Abstract

Abstract: BACKGROUND: Osteonecrosis is a chronic orthopedic disease characterized by ischemic necrosis of bone tissue. Current treatment methods can delay the disease progression, but cannot completely cure it. There is an urgent need to explore new therapeutic targets. Against this backdrop, the development of omics technologies has provided effective tools for analyzing the genetic mechanisms of complex diseases. Among them, expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS) data can reveal the impact of genetic variations on gene expression.
OBJECTIVE: To explore the potential protective role of the Carboxypeptidase M gene in osteonecrosis, evaluate its possibility as a new therapeutic target, and provide a theoretical basis for the precision treatment of osteonecrosis.
METHODS: Two-sample Mendelian randomization analysis was adopted, integrating two international databases: eQTLGen and FinnGen GWAS. eQTLGen was jointly established by the University of Groningen in the Netherlands and the University of Tartu in Estonia, covering 31 684 European populations, which focuses on revealing the regulatory effect of genetic variations on gene expression. The FinnGen GWAS database was constructed by the Finnish Biobank in collaboration with multiple research institutions, containing 1 788 osteonecrosis patients and 429 826 controls, dedicated to in-depth research on the association between disease phenotypes and genotypes. This study systematically screened 2 534 druggable genes in the eQTL database and found that the eQTL signal of the Carboxypeptidase M gene shared causal variations with the GWAS signal of osteonecrosis. Sensitivity analyses (including heterogeneity detection, horizontal pleiotropy assessment, and leave-one-out analysis) and colocalization analysis were carried out to ensure the robustness and reliability of the results.
RESULTS AND CONCLUSION: The study found that the Carboxypeptidase M gene was significantly associated with osteonecrosis, and its high expression could significantly reduce the risk of osteonecrosis (odds ratio < 1, false discovery rate < 0.05). Colocalization analysis confirmed that the eQTL signal of the Carboxypeptidase M gene shared causal variations with the GWAS signal of osteonecrosis (PP.H4=98.03%). This study is the first to reveal the protective role of the Carboxypeptidase M gene in osteonecrosis, clarifying its value as a potential therapeutic target and providing a solid basis for the precision treatment of osteonecrosis. It has important implications for basic and clinical medical research in China.

Key words: osteonecrosis, Carboxypeptidase M, expression quantitative trait locus, Mendelian randomization, genome-wide association studies, therapeutic targets, druggable genes, colocalization analysis

CLC Number:

Gao Xinhai, Tan Huangsheng, He Shenghua. Carboxypeptidase M: unveiling a new therapeutic target for osteonecrosis based on eQTL Database and Finnish Genetic Big Data[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(11): 2870-2876.

Figures/Tables 3

2.1 工具变量筛选与孟德尔随机化分析结果根据工具变量的选择标准，共筛选出2 534个可成药基因的39 155个单核苷酸多态性作为工具变量，这些单核苷酸多态性与暴露均具有显著的关联性，且所有工具变量的F值均超过20，最低为29.72，平均值为186.39，表明工具变量的效能较强，能够满足孟德尔随机化分析的假设要求。基于逆方差加权法的孟德尔随机化分析结果显示，有317个可成药基因的表达水平与骨坏死显著相关(P < 0.05)。其中，4个可成药基因通过FDR多重检验校正(FDR < 0.05)，分别为CSK、EPHB4、ADCK3和CPM，见表2。此外，采用多种方法评估CPM、CSK、EPHB4和ADCK3基因高表达对骨坏死风险的保护作用。逆方差加权法分析显示，这4个基因的高表达均与骨坏死风险的显著降低相关，其中CPM基因的OR=0.47 (95%CI：0.34-0.66，P=1.10×10-5)，CSK基因OR=0.74(95%CI：0.66-0.83，P=4.95×10??)，EPHB4基因OR=0.85(95%CI：0.79-0.91，P=4.40×10??)，ADCK3基因OR=0.89(95%CI：0.84-0.93，P=6.47×10-6)，见图2。为验证结果的稳健性，进一步采用MR-Egger和加权中位数法进行分析。加权中位数法的结果与主要分析一致，4个基因均显示出显著的保护作用，见表3。在CSK、CPM基因中，MR-Egger效应估计值未达到统计显著性。通过留一法对工具变量进行敏感性分析，结果表明，逐一排除每个工具变量后，4个基因的整体效应估计值无明显变化，验证了分析结果的稳健性。 2.2 异常结果处理与敏感性分析在MR-Egger回归分析中发现，EPHB4基因存在显著水平的多效性，Cochran’s Q检验结果表明，CSK基因可能存在异质性，暗示这些基因未完全满足孟德尔随机化分析的假设要求。因此，为提高分析结果的准确性和稳健性，在后续分析中排除了EPHB4和CSK基因。 2.3 反向孟德尔随机化在反向孟德尔随机化分析中，以骨坏死为暴露变量、血液中基因表达的cis-eQTL为结局变量，对CPM基因和ADCK3基因"

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