血浆蛋白与骨质疏松症的关系及潜在治疗靶点:基于国际UK Biobank数据库信息

Association between plasma proteins and osteoporosis and identification of potential therapeutic targets:information analysis based on the UK Biobank database

背景:骨质疏松症是全球范围内增加疾病负担和致残率的重要因素。血浆蛋白参与体内复杂的生物过程,在揭示疾病机制和发现潜在治疗靶点方面起着关键作用。尽管已有研究显示血浆蛋白与骨质疏松症之间存在关联,但这些关联的因果性质尚未得到充分阐明。因此,利用大规模的血浆蛋白数据探究与骨质疏松症相关的因果蛋白并识别潜在的药物靶点,对于骨质疏松症的防治至关重要。目的:运用两样本孟德尔随机化分析,以国际UK Biobank数据库为来源信息,评估血浆蛋白与骨质疏松症之间的因果关联。方法:从UK Biobank数据库获取1001种血浆蛋白相关的全基因组显著性水平(P<5×10-8)的蛋白质数量性状位点作为工具变量,并排除连锁不平衡。骨质疏松症的汇总数据来自FinnGen数据库,共涉及438872名欧洲血统个体。研究采用逆方差加权、MR-Egger回归、加权中位数等方法进行分析,并进行多项敏感性分析以确保结果的稳健性。进一步构建蛋白-蛋白互作网络,结合基因本体富集分析和京都基因与基因组百科全书通路分析,探索血浆蛋白的功能相关性及潜在作用机制。结果与结论:①孟德尔随机化逆方差加权法结果显示有50种血浆蛋白与骨质疏松症存在因果关系(P<0.05),包括染色体19开放阅读框12(chromosome 19 open reading frame 12,C19orf12;OR=0.610,95%CI:0.483-0.769,P=2.967×10-5)、表皮生长因子(OR=0.877,95%CI:0.770-0.999,P=0.049)等20种血浆蛋白可能与骨质疏松症的风险降低相关,有CCL18(OR=1.091,95%CI:1.037-1.147,P=0.001)、CD209(OR=1.036,95%CI:1.003-1.070,P=0.034)等30种血浆蛋白可能增加骨质疏松症的风险,经Bonferroni校正后,只有C19orf12与骨质疏松症存在显著的因果关联。②多项敏感性分析显示研究不存在多效性和异质性,说明结果具有稳健性。③通过构建蛋白-蛋白互作网络明确了表皮生长因子、CCL5、CXCL13、CXCL5、血管内皮生长因子C、CCL18、CCL17、TEK受体酪氨酸激酶、含免疫球蛋白样和表皮生长因子样结构域的酪氨酸激酶1(TIE1)和CCL23为核心蛋白。④基因本体富集分析和京都基因与基因组百科全书通路分析表明这些血浆蛋白在免疫系统中具有重要作用,通过参与信号传导、细胞迁移和趋化等过程影响骨质疏松症。⑤文章结果揭示了1001种血浆蛋白与骨质疏松症的潜在因果关联,这种基于大规模数据驱动的分析方法有助于在中国人群中识别新的生物标志物和药物靶点;其次,文章结果表明,免疫系统信号传导、细胞迁移和趋化等过程在骨质疏松症发病机制中发挥重要作用,这为特定遗传背景和环境因素下的骨质疏松症研究提供了新的方向;最后,研究中识别的核心蛋白(如表皮生长因子、CCL5及CXCL13等)有望成为新的生物标志物或药物靶点,为骨质疏松症的精准防治提供新的依据。

BACKGROUND:Osteoporosis is a significant contributor to the global burden of disease and disability.Plasma proteins are involved in complex biological processes and play a crucial role in uncovering disease mechanisms and identifying potential therapeutic targets.Although existing studies have suggested an association between plasma proteins and osteoporosis,the causal nature of these associations is not fully clarified.Therefore,it is imperative to identify the causal proteins associated with osteoporosis and potential therapeutic targets for the amelioration and management of this condition using large-scale plasma protein data.OBJECTIVE:To evaluate the causal relationship between plasma proteins and osteoporosis based on the UK Biobank database as source information using the two-sample Mendelian randomization.METHODS:A total of 1001 plasma protein-related genome-wide significant quantitative trait loci(P<5×10-8)were obtained from the UK Biobank database and used as instrumental variables,with linkage disequilibrium excluded.Summary data on osteoporosis were collected from the FinnGen database,which included 438872 individuals of European descent.The study was analyzed using inverse variance weighting,MR-Egger regression,weighted median,and several sensitivity analyses to ensure the robustness of the results.Further,a protein-protein interaction network was constructed,and Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to explore the functional relevance and potential mechanisms of plasma proteins.RESULTS AND CONCLUSION:(1)The Mendelian randomization analysis using the inverse variance weighted method identified 50 plasma proteins that have causal associations with osteoporosis(P<0.05).Among them,20 plasma proteins,including chromosome 19 open reading frame 12(odds ratio[OR]=0.610;95%confidence interval[CI]:0.483-0.769,P=2.967×10-5)and epidermal growth factor(EGF;OR=0.877;95%CI:0.770-0.999,P=0.049),might be associated with a reduced risk of osteoporosis.In contrast,30 plasma proteins,such as C-C motif chemokine ligand(CCL)18(OR=1.091;95%CI:1.037-1.147,P=0.001)and CD209(OR=1.036;95%CI:1.003-1.070,P=0.034),might be associated with an increased risk of osteoporosis.After Bonferroni correction,only chromosome 19 open reading frame 12 showed a significant causal association with osteoporosis.(2)Multiple sensitivity analyses revealed no evidence of pleiotropy or heterogeneity,indicating the robustness of the results.(3)The construction of the PPI network identified core proteins such as EGF,CCL5,C-X-C motif chemokine ligand(CXCL)13,CXCL5,vascular endothelial growth factor C,CCL17,CCL18,TEK receptor tyrosine kinase,tyrosine kinase with immunoglobulin like and EGF like domains 1,and CCL23.(4)Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that these plasma proteins play essential roles in the immune system,influencing osteoporosis through processes such as signal transduction,cell migration,and chemotaxis.(5)This study reveals the potential causal associations between 1001 plasma proteins and osteoporosis,highlighting the utility of a large-scale,data-driven approach to identify new biomarkers and drug targets in diverse populations.Additionally,our findings suggest that processes such as immune signaling,cell migration,and chemotaxis play significant roles in the pathogenesis of osteoporosis,offering new directions for research under specific genetic backgrounds and environmental factors.Finally,the core proteins identified in this study(e.g.,EGF,CCL5,and CXCL13)may serve as novel biomarkers or therapeutic targets,providing a new basis for the precise prevention and treatment of osteoporosis.