中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (33): 8607-8617.doi: 10.12307/2026.394

• 骨组织构建 bone tissue construction • 上一篇    下一篇

中介血浆蛋白Alpha-2-HS-糖蛋白调节乳糜泻对骨质疏松症的影响及预测效能分析

段煜东，赵丕乾，过倩萍，谢计乐   

  1. 苏州大学附属第一医院骨科，苏州大学骨科研究所，江苏省苏州市   215006

  • 收稿日期:2025-06-06 修回日期:2025-10-20 出版日期:2026-11-28 发布日期:2026-06-09
  • 通讯作者: 谢计乐，博士，主治医师，苏州大学附属第一医院骨科，苏州大学骨科研究所，江苏省苏州市 215006
  • 作者简介:段煜东，男，1998年生，江西省吉安市人，汉族，苏州大学附属第一医院在读硕士，主要从事骨代谢相关疾病研究。 并列第一作者：赵丕乾，男，1998年生，山东省青岛市人，汉族，硕士，主要从事骨质疏松方面的研究。
  • 基金资助:
    苏州市姑苏医学人才计划(GSWS2023087)，项目负责人：谢计乐

Regulatory role of mediating plasma protein alpha-2-HS glycoprotein in celiac disease and its predictive efficacy analysis for osteoporosis

Duan Yudong, Zhao Piqian, Guo Qianping, Xie Jile   

  1. Department of Orthopedics, First Affiliated Hospital of Soochow University; Institute of Orthopedics, Soochow University, Suzhou 215006, Jiangsu Province, China 
  • Received:2025-06-06 Revised:2025-10-20 Online:2026-11-28 Published:2026-06-09
  • Contact: Xie Jile, MD, Attending physician, Department of Orthopedics, First Affiliated Hospital of Soochow University; Institute of Orthopedics, Soochow University, Suzhou 215006, Jiangsu Province, China
  • About author:Duan Yudong, Master candidate, Department of Orthopedics, First Affiliated Hospital of Soochow University; Institute of Orthopedics, Soochow University, Suzhou 215006, Jiangsu Province, China Zhao Piqian, MS, Department of Orthopedics, First Affiliated Hospital of Soochow University; Institute of Orthopedics, Soochow University, Suzhou 215006, Jiangsu Province, China
  • Supported by:
    Suzhou Gusu Medical Talent Program, No. GSWS2023087 (to XJL).

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摘要：



文题释义：
Alpha-2-HS-糖蛋白：是由肝脏合成的血浆糖蛋白，参与骨代谢、免疫调节和炎症反应。它通过调控成骨细胞分化和结合钙磷离子影响骨矿化，对成骨细胞和破骨细胞活性具有双向调节作用。在骨质疏松症中，Alpha-2-HS-糖蛋白功能异常与骨密度下降密切相关，尤其在糖尿病患者中，Alpha-2-HS-糖蛋白调控失衡可能加剧骨微结构破坏。遗传学研究显示，特定基因变异会降低Alpha-2-HS-糖蛋白表达，增加骨折风险。这些发现表明Alpha-2-HS-糖蛋白不仅是骨代谢的关键调节因子，还可能成为糖尿病相关骨质疏松的潜在治疗靶点。
乳糜泻：是一种由麸质摄入引发的自身免疫性疾病，主要表现为小肠黏膜损伤和营养吸收障碍，乳糜泻发病机制与机体对麸质产生异常免疫反应有关，患者体内产生抗组织转谷氨酰胺酶抗体，导致肠道炎症和绒毛萎缩。值得注意的是，乳糜泻患者的骨质疏松风险不仅源于钙和维生素D吸收不良，更与免疫系统直接激活骨破坏机制相关。麸质代谢产物通过免疫信号通路异常激活破骨细胞，打破骨形成与吸收的平衡，加速骨量流失。

背景：近年来，有研究表明乳糜泻与骨质疏松症之间存在关联。然而，这一关联的因果性质尚未得到充分证实，需要更多数据支持以加强骨质疏松症的预防和管理。
目的：采用横断面分析与孟德尔随机化相结合的方法，探讨乳糜泻与骨质疏松症之间的因果关系，并筛选可能介导这一关系的血浆蛋白，以揭示潜在机制。
方法：研究采用多阶段分析方法探讨乳糜泻与骨质疏松症的关联及潜在机制。首先，通过Logistic回归分析评估乳糜泻患者的骨质疏松症风险。随后，基于双样本孟德尔随机化方法，利用IEU OpenGWAS和Finngen R10两大公开数据库的数据，深入探究乳糜泻与骨质疏松症之间的因果关系。IEU OpenGWAS数据库由英国埃克塞特大学建立，该数据库整合了多种全基因组关联研究数据，为遗传学研究提供开放资源支持，其中乳糜泻数据集(GCST90014442)包含2 364例病例和324 074例对照；Finngen R10数据库由芬兰生物银行网络构建，该数据库专门为芬兰人群健康数据提供支持，研究采用的骨质疏松症数据集包含8 017例患者和391 037例对照。该研究基于公开可用的汇总统计数据库，无需伦理审批。为进一步阐明潜在机制，采用deCODE和UKBPPP数据库进行共定位分析，筛选可能的中介血浆蛋白。通过基因表达分析探讨这些蛋白在乳糜泻患者中的表达变化趋势，并运用受试者工作特征曲线评估其诊断价值。
结果与结论：①Logistic回归分析显示，乳糜泻患者发生骨质疏松症的风险较非乳糜泻患者明显增加(OR=56.000，P=0.008)；②孟德尔随机化分析进一步表明乳糜泻与骨质疏松症之间存在因果效应(OR=2.363，P < 0.01)；③共定位分析显示Alpha-2-HS-糖蛋白是关键中介因素(PPH3+PPH4=0.862，PPH4=0.793)，基因表达检测结果显示，乳糜泻患者Alpha-2-HS-糖蛋白的表达水平显著升高，并与骨矿物质密度呈显著负相关(r=-0.805，P < 0.05)；④受试者工作特征曲线分析显示Alpha-2-HS-糖蛋白具有一定的诊断效能，曲线下面积为0.667，尤其在联合其他生物标志物时，其诊断效能进一步提高(曲线下面积为0.706)。此研究揭示了乳糜泻患者骨质疏松症风险增加的可能机制，并提出Alpha-2-HS-糖蛋白作为潜在的关键中介因素，可能在乳糜泻相关骨质疏松症的早期诊断和风险评估中发挥重要作用，为乳糜泻患者骨质疏松症的防治提供了新的生物标志物和潜在干预靶点，为临床实践提供了重要参考。
https://orcid.org/0009-0004-4337-4579 (段煜东)；https://orcid.org/0009-0004-9631-8482 (谢计乐)


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 乳糜泻, 骨质疏松症, 孟德尔随机化, Alpha-2-HS-糖蛋白(AHSG), 受试者工作特征曲线

Abstract: BACKGROUND: Recent studies have suggested an association between celiac disease and osteoporosis. However, the causal nature of this association has not been fully established. More evidence is required to enhance the prevention and treatment of osteoporosis.
OBJECTIVE: To investigate the causal relationship between celiac disease and osteoporosis and to screen plasma proteins that may mediate this relationship to reveal the underlying mechanisms through a combination of cross-sectional analysis and Mendelian randomization.
METHODS: A multi-stage analytical approach was used to analyze the association between celiac disease and osteoporosis and its underlying mechanisms. Initially, logistic regression analysis was used to assess the risk of osteoporosis in patients with celiac disease. Subsequently, a two-sample Mendelian randomization analysis was applied to delve into the causal relationship between celiac disease and osteoporosis, leveraging data from two major databases: IEU OpenGWAS and Finngen R10. In terms of data sources, the study primarily relied on two authoritative databases. The first, the IEU OpenGWAS database, established by the University of Exeter, UK, aggregates a variety of genome-wide association study data, providing open resource support for genetic research. The celiac disease dataset used (GCST90014442) comprised 2 364 cases and 324 074 controls. The second, the Finngen R10 database, constructed by the Finnish Biobank Network, specializes in providing health data support for the Finnish population. For this study, the osteoporosis dataset included 8 017 patients and 391,037 controls. As this study uses publicly available aggregated statistical databases, it is exempt from ethical approval. To further elucidate the potential mechanisms, the study conducted colocalization analysis using the deCODE and UKBPPP databases to screen for possible mediating plasma proteins. Gene expression analysis was performed to explore the expression trends of these proteins in patients with celiac disease, and the diagnostic value was assessed using receiver operating characteristic curves.
RESULTS AND CONCLUSION: (1) Logistic regression analysis showed that the risk of osteoporosis was significantly increased in patients with celiac disease compared with those without celiac disease (OR=56.000, P=0.008). (2) Mendelian randomization analysis further indicated that there was a causal effect between celiac disease and osteoporosis (OR=2.363, P < 0.01). (3) Colocalization analysis showed that alpha-2-HS glycoprotein (AHSG) is a mediating factor (PPH3+PPH4=0.862, PPH4=0.793). The results of gene expression detection showed that the expression level of AHSG was significantly increased in patients with celiac disease, and was significantly negatively correlated with bone mineral density (r=-0.805, P < 0.05). (4) Receiver operating characteristic curve analysis showed that AHSG had a certain diagnostic efficiency, and the area under the curve (AUC) was 0.667, especially when combined with other biomarkers, the diagnostic efficiency was further improved (AUC=0.706). This study reveals a possible mechanism for the increased risk of osteoporosis in patients with celiac disease and suggests AHSG as a potential key mediator that may play an important role in the early diagnosis and risk assessment of celiac disease-associated osteoporosis. These findings provide new biomarkers and potential intervention targets for the prevention and treatment of osteoporosis in patients with celiac disease, and provide an important reference for clinical practice.


Key words: celiac disease, osteoporosis, Mendelian randomization, alpha-2-HS glycoprotein (AHSG), receiver operating characteristic curve

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