Wu Zhichong, Yang Kenneth Guangpu, Lam Tsz-Ping, Cheng Jack Chun Yiu, Zhu Zezhang, Lee Wayne Yuk-Wai
Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Musculoskeletal Research Laboratory, SH Ho Scoliosis Research Laboratory, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Front Genet. 2023 Jun 28;14:1161817. doi: 10.3389/fgene.2023.1161817. eCollection 2023.
Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) ( < 4 × 10). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, = 1.6 × 10), collagen binding (GO:0005518, = 8.6 × 10), and extracellular matrix structural constituent (GO:0005201, = 2.7 × 10). The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.
骨质疏松症是全球疾病负担和残疾的主要致病因素，其特征为骨矿物质密度（BMD）低和骨折风险高。我们旨在确定骨质疏松症的潜在因果蛋白和可成药靶点。本研究利用了关于血浆蛋白和估算足跟骨密度（eBMD）的最大全基因组关联研究（GWAS）汇总统计数据，通过孟德尔随机化（MR）分析来确定骨质疏松症的因果蛋白。使用不同的GWAS数据集来验证结果。进行了多项敏感性分析以评估主要MR结果的稳健性。我们还对鉴定出的因果蛋白进行了富集分析，并评估了它们的可成药性。经过Bonferroni校正后，确定有67种蛋白与估算骨密度（eBMD）存在因果关联（<4×10）。我们进一步复制了67种蛋白中的38种，发现它们与全身骨密度、腰椎骨密度、股骨颈骨密度以及骨折相关，如RSPO3、IDUA、SMOC2和LRP4。敏感性分析支持了这些发现。富集分析确定了多个基因本体条目，包括含胶原蛋白的细胞外基质（GO:0062023，=1.6×10）、胶原蛋白结合（GO:0005518，=8.6×10）和细胞外基质结构成分（GO:（此处原文可能有误，推测为GO:0005201，=2.7×10）。该研究确定了骨质疏松症新的潜在因果蛋白，这些蛋白可能作为潜在的早期筛查生物标志物和可成药靶点。此外，强调了参与胶原蛋白结合和细胞外基质的血浆蛋白在骨质疏松症发展中的作用。有必要进一步开展研究以验证我们的发现并探究其潜在机制。
