Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, United States.
Geriatric Research Education and Clinical Center, VA Health Care System, Minneapolis, MN, 56401, United States.
J Bone Miner Res. 2024 Mar 22;39(2):139-149. doi: 10.1093/jbmr/zjad011.
Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.
髋部骨折与显著的残疾、高成本和高死亡率相关。然而，导致髋部骨折易感性的具体生物学机制仍不完全清楚。在对循环蛋白质组学进行的探索性研究中，我们对髋部骨折的发病情况进行了全面的循环蛋白质组关联研究（CPAS）荟萃分析。分析包括来自两项前瞻性队列研究（心血管健康研究和特隆德拉格健康研究）的 6430 名受试者，这些研究有循环蛋白质组学数据（基于适体的 5K SomaScan 版本 4.0 检测法；4979 个适体）。使用年龄和性别调整的 Cox 回归模型，对每个队列中循环蛋白水平与髋部骨折发病之间的关系进行了估计。研究共发生 643 例髋部骨折。与个体研究相比，逆方差加权荟萃分析产生了更多具有统计学意义的关联，确定了 23 个与髋部骨折发病相关的适体（保守的 Bonferroni 校正 0.05/4979，P<1.0×10-5）。与髋部骨折风险相关性最强的适体对应于生长激素/胰岛素样生长因子系统的两种蛋白（GHR 和 IGFBP2），以及 GDF15 和 EGFR。几种与炎症相关的蛋白（CD14、CXCL12、MMP12、ITIH3）水平较高也与髋部骨折风险增加相关。通路分析鉴定出，与髋部骨折风险增加相关的蛋白中，LXR/RXR 激活减少和急性期反应信号增加占主导地位。这些分析确定了几种与髋部骨折发病情况相关的循环蛋白和通路。这些发现强调了荟萃分析方法在全面 CPAS 中的有效性，类似于先前在大规模人类遗传研究中观察到的那样。未来的研究应深入研究这些潜在的新型药物靶点的生物学基础。
