摘要
背景:骨坏死是一种以骨组织缺血性坏死为特征的慢性骨科疾病,现有治疗手段虽能延缓疾病进展,但无法彻底治愈,亟需探索新的治疗靶点。基于此背景,组学技术的发展为解析复杂疾病的遗传机制提供了有效工具,其中表达数量性状位点数据和全基因组关联研究数据能够揭示遗传变异对基因表达的影响。目的:探索羧肽酶M基因在骨坏死中的潜在保护作用,评估其作为新的治疗靶点的可能性,并为骨坏死的精准治疗提供理论依据。方法:采用双样本孟德尔随机化分析,整合了2个国际数据库:eQTLGen和FinnGen GWAS。eQTLGen由荷兰格罗宁根大学和爱沙尼亚塔图尔大学联合建设,涵盖31684名欧洲人群,专注于揭示遗传变异对基因表达的调控作用;FinnGen GWAS数据库由芬兰生物银行联合多家科研机构构建,包含1788例骨坏死患者与429826名对照,致力于疾病表型和基因型的深度关联研究。对表达数量性状位点数据库中2534个可成药基因进行系统筛选,发现了羧肽酶M基因的表达数量性状位点信号与骨坏死全基因组关联研究信号共享因果变异。结合敏感性分析(包括异质性检测、水平多效应评估和留一法分析)、共定位分析进一步验证结果的可靠性和稳健性。结果与结论:研究发现羧肽酶M基因与骨坏死显著相关,羧肽酶M高表达可显著降低骨坏死风险(OR<1,错误发现率<0.05)。共定位分析证实,羧肽酶M的表达数量性状位点信号与骨坏死的全基因组关联研究信号共享因果变异(PP.H4=98.03%)。首次揭示了羧肽酶M基因在骨坏死中的保护作用,明确它作为潜在治疗靶点的价值,为骨坏死的精准治疗提供了坚实依据,对中国基础医学和临床医学研究具有重要的借鉴意义。
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 31684 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 1788 osteonecrosis patients and 429826 controls,dedicated to in-depth research on the association between disease phenotypes and genotypes.This study systematically screened 2534 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.
作者
高鑫海
谭黄圣
何升华
Gao Xinhai;Tan Huangsheng;He Shenghua(The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen 518000,Guangdong Province,China;The Second Ward of the Orthopedics and Traumatology Department,Shenzhen Hospital of Traditional Chinese Medicine,Shenzhen 518000,Guangdong Province,China)
出处
《中国组织工程研究》
北大核心
2026年第11期2870-2876,共7页
Chinese Journal of Tissue Engineering Research
基金
深圳市“医疗卫生三名工程”项目(SZZYSM202211004),项目负责人:何升华。
关键词
骨坏死
羧肽酶M
表达数量性状位点
孟德尔随机化
全基因组关联研究
治疗靶点
可用药基因
共定位分析
osteonecrosis
Carboxypeptidase M
expression quantitative trait locus
Mendelian randomization
genome-wide association studies
therapeutic targets
druggable genes
colocalization analysis
