Meng Chen, Ren Junxiao, Gu Honglin, Shi Hongxin, Luo Huan, Wang Zhihao, Li Chuan, Xu Yongqing
School of Graduate, Kunming Medical University, Kunming, Yunnan, China.
Department of Orthopaedic, 920th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Kunming, Yunnan, China.
Front Genet. 2024 Jul 25;15:1440062. doi: 10.3389/fgene.2024.1440062. eCollection 2024.
Previous studies have explored the role of plasma proteins on osteonecrosis. This Mendelian randomization (MR) study further assessed plasma proteins on osteonecrosis whether a causal relationship exists and provides some evidence of causality.
Summary-level data of 4,907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals by the deCODE Genetics Consortium. The outcome data for osteonecrosis were sourced from the FinnGen study, comprising 1,543 cases and 391,037 controls. MR analysis was conducted to estimate the associations between protein and osteonecrosis risk. Additionally, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets.
We totally assessed the effect of 1,676 plasma proteins on osteonecrosis risk, of which 71 plasma proteins had a suggestive association with outcome risk ( < 0.05). Notably, Heme-binding protein 1 (HEBP1) was significant positively associated with osteonecrosis risk with convening evidence (OR, 1.40, 95% CI, 1.19 to 1.65, = 3.96 × 10, = 0.044). This association was further confirmed in other MR analysis methods and did not detect heterogeneity and pleiotropy (all > 0.05). To comprehensively explore the health effect of HEBP1, the phenome-wide MR analysis found it was associated with 136 phenotypes excluding osteonecrosis ( < 0.05). However, no significant association was observed after the false discovery rate adjustment.
This comprehensive MR study identifies 71 plasma proteins associated with osteonecrosis, with HEBP1, ITIH1, SMOC1, and CREG1 showing potential as biomarkers of osteonecrosis. Nonetheless, further studies are needed to validate this candidate plasma protein.
以往的研究探讨了血浆蛋白在骨坏死中的作用。这项孟德尔随机化（MR）研究进一步评估了血浆蛋白与骨坏死之间是否存在因果关系，并提供了一些因果关系的证据。
通过deCODE基因联盟，从一项包括35559名个体的大规模蛋白质定量性状位点研究中提取了4907种循环蛋白水平的汇总数据。骨坏死的结局数据来自芬兰基因研究，包括1543例病例和391037例对照。进行MR分析以估计蛋白质与骨坏死风险之间的关联。此外，采用全表型MR分析和候选药物预测来识别潜在的因果循环蛋白和新的药物靶点。
我们总共评估了1676种血浆蛋白对骨坏死风险的影响，其中71种血浆蛋白与结局风险有提示性关联（<0.05）。值得注意的是，血红素结合蛋白1（HEBP1）与骨坏死风险呈显著正相关，证据确凿（OR，1.40，95%CI，1.19至1.65，=3.96×10，=0.044）。这种关联在其他MR分析方法中得到了进一步证实，且未检测到异质性和多效性（均>0.05）。为了全面探索HEBP1的健康效应，全表型MR分析发现它与除骨坏死外的136种表型相关（<0.05）。然而，在错误发现率调整后未观察到显著关联。
这项全面的MR研究确定了71种与骨坏死相关的血浆蛋白，其中HEBP1、ITIH1、SMOC1和CREG1显示出作为骨坏死生物标志物的潜力。尽管如此，仍需要进一步的研究来验证这些候选血浆蛋白。
