中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (4): 1047-1057.doi: 10.12307/2025.944

• 组织构建循证医学 evidence-based medicine in tissue construction • 上一篇    下一篇

循环炎症蛋白与心肌肥厚：来自GWAS Catalog与芬兰数据库欧洲群体的大样本分析

丁  宇1，陈婧雯2，陈秀燕1，施慧敏1，杨雨蝶1，周美启3，崔  帅1，3   

  1. 1安徽中医药大学针灸推拿学院，安徽省合肥市  230001；2南京医科大学第一附属医院，江苏省南京市  210000；3经脉脏腑相关安徽省重点实验室，安徽省合肥市  230001
  • 收稿日期:2024-10-15 接受日期:2024-12-12 出版日期:2026-02-08 发布日期:2025-05-23
  • 通讯作者: 崔帅，博士，教授，安徽中医药大学针灸推拿学院，安徽省合肥市 230001
  • 作者简介:丁宇，女，1999年生，浙江省绍兴市人，汉族，安徽中医药大学针灸推拿专业在读硕士，主要从事心血管疾病方面的研究。
  • 基金资助:
    国家重点研发计划课题(2022YFC3500502)，项目负责人：周美启；优秀青年教师培育重点项目(YQZD2023046)，项目负责人：崔帅

Circulating inflammatory proteins and myocardial hypertrophy: large sample analysis of European populations from GWAS Catalog and FinnGen databases

Ding Yu1, Chen Jingwen2, Chen Xiuyan1, Shi Huimin1, Yang Yudie1, Zhou Meiqi3, Cui Shuai1, 3   

  1. 1College of Acupuncture and Massage, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China; 2First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China; 3Anhui Provincial Key Laboratory of Meridian-Organ Correlation, Hefei 230001, Anhui Province, China 
  • Received:2024-10-15 Accepted:2024-12-12 Online:2026-02-08 Published:2025-05-23
  • Contact: Cui Shuai, MD, Profesosr, College of Acupuncture and Massage, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China; Anhui Provincial Key Laboratory of Meridian-Organ Correlation, Hefei 230001, Anhui Province, China
  • About author:Ding Yu, Master candidate, College of Acupuncture and Massage, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China
  • Supported by:
    National Key Research & Development Program, No. 2022YFC3500502 (to ZMQ); Key Project for Cultivating Outstanding Young Teachers, No. YQZD2023046 (to CS)

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摘要：


文题释义：
心肌肥厚：是指心肌细胞体积增大，导致心脏壁厚度增加的一种病理或生理现象，这种现象可以发生在左心室、右心室或两者同时发生。心肌肥厚一般是由于心脏长期受到过大的负荷引起的，常见的原因包括高血压、心脏瓣膜疾病、先天性心脏病以及运动员的高强度训练等。
孟德尔随机化：是一种基于遗传学的统计方法，用于评估暴露因素(如环境因素、行为或生物标志物)与疾病结果之间的因果关系。它利用遗传变异作为工具变量，帮助研究者排除混杂因素的影响，并减少反向因果关系的偏差。

背景：心肌肥厚常会导致严重的心血管疾病，由于早期难以被发现，因此很难确诊。循环炎症蛋白被发现与心血管疾病有相当大的关联，但其与心肌肥厚关系的具体机制依然不明确。
目的：采用多种孟德尔随机化的方法探究循环炎症蛋白和心肌肥厚间的关系。
方法：采用GWAS Catalog数据库中的91个循环炎症蛋白数据库和最新版R11芬兰数据库中的心肌肥厚数据，利用双向两样本孟德尔随机化、多变量孟德尔随机化和全基因组关联研究共定位分析的方式探寻循环炎症蛋白和心肌肥厚的因果关系。用MR-PRESSO方法、Cochran’s Q检验、MR-Egger截距评估、留一法分析和漏斗图分析等敏感性检验的方式验证结果的准确性。
结果与结论：①在双向两样本孟德尔随机化结果中主要用逆方差加权法(Inverse Variance Weighting，IVW)进行评估，发现T细胞表面糖蛋白CD6异构体水平(IVW：P=0.046，OR=0.74，95%CI：0.66-1.00)，裂隙趋化因子水平(IVW：P=2.1×10-2，OR=0.74，95%CI：0.556-0.95)，Delta和Notch样表皮生长因子相关受体水平(IVW：P=3.7×10-4，OR=0.66，95%CI：0.49-0.87)，白细胞介素2水平(IVW：P=3.8×10-3，
OR=0.667，95%CI：0.50-0.88)，硫酸转移酶1A1(IVW：P=1.42×10-2，OR=0.80，95%CI：0.67-0.96)对心肌肥厚具有单向因果作用。②在多变量孟德尔随机化中发现，T细胞表面糖蛋白CD6异构体水平(IVW：P=1.39×10-2，OR=0.81，95%CI：0.69-0.96)和Delta和Notch样表皮生长因子相关受体水平(IVW：P=3.7×10-2，OR=0.73，95%CI：0.55-0.98)的结果为阳性，说明排除了其他和心肌肥厚具有影响的循环炎症蛋白影响后其结果依然显著。③在共定位中发现，T细胞表面糖蛋白CD6异构体水平H3+H4=0.96，其中最显著的单核苷酸多态性为rs59570070，说明T细胞表面糖蛋白CD6异构体水平和心肌肥厚存在内在联系。④敏感性结果无异常，说明无异质性和多效性影响结果。⑤结果证实，T细胞表面糖蛋白CD6异构体、裂隙趋化因子、Delta和Notch样表皮生长因子相关受体、白细胞介素2、硫酸转移酶1A1对心肌肥厚具有单向因果作用。T细胞表面糖蛋白CD6异构体和Delta和Notch样表皮生长因子相关受体影响最深，T细胞表面糖蛋白CD6异构体和心肌肥厚之间可能存在相关通路。由于孟德尔随机化研究需要大量的临床数据，因此常采用国际数据库中的欧洲样本分析，由于该分析方法在因果推断、精准医学及跨人群验证等方面具有重要优势，因此其研究结果对中国医学发展仍有重要意义。随着孟德尔随机化研究的深入，在一定意义上也推动了中国临床数据的收集和分析。未来可深入解析关键蛋白机制，结合多组学和临床验证，开发炎症标志物监测体系及新型抗炎疗法，从而推动心血管疾病的防控和个性化医疗发展。
https://orcid.org/0009-0005-8348-9634(丁宇)；https://orcid.org/0000-0003-1457-6759(崔帅)

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: 心肌肥厚, 循环炎症蛋白, 心血管疾病, 孟德尔随机化, 因果关系, 观察性研究, 共定位, 多变量孟德尔随机化

Abstract: BACKGROUND: Myocardial hypertrophy often leads to severe cardiovascular diseases and is difficult to diagnose due to its early stages being hard to detect. Circulating inflammatory proteins have been found to be significantly associated with cardiovascular diseases, yet the specific mechanisms linking them to myocardial hypertrophy remain unclear. 
OBJECTIVE: To investigate the relationship between circulating proteins and myocardial hypertrophy using multiple Mendelian randomization approaches.
METHODS: Utilizing data from 91 circulating inflammatory proteins in the GWAS Catalog database and the latest myocardial hypertrophy data from the R11 FinnGen database, we employed bidirectional two-sample Mendelian randomization, multivariate Mendelian randomization, and Genome-Wide Association Studies co-localization to investigate the causal relationship between circulating inflammatory proteins and myocardial hypertrophy. The accuracy of the results was verified through sensitivity tests including MR-PRESSO, Cochran’s Q test, MR-Egger intercept assessment, leave-one-out analysis, and funnel plot analysis.
RESULTS AND CONCLUSION: In the results of two-sample Mendelian randomization, the primary method used for evaluation was the Inverse Variance Weighting (IVW) approach. It was found that the level of T-cell surface glycoprotein CD6 isoform (IVW: P=0.046, OR=0.74, 95% CI: 0.66-1.00), level of slit chemokine (IVW: P=2.1×10-2, OR=0.74, 95%CI: 0.556-0.95), level of Delta and Notch-like epidermal growth factor-related receptor (IVW: P=3.7×10-4, OR=0.66, 95% CI: 0.49-0.87), level of interleukin-2 (IVW: P=3.8×10-3, OR=0.667, 95%CI: 0.50-0.88), and sulfotransferase 1A1 (IVW: P=1.42×10-2, OR=0.80, 95% CI: 0.67-0.96) had a unidirectional causal effect on cardiac hypertrophy. (2) Among the findings in multivariate Mendelian randomization, the levels of the CD6 isoform of T-cell surface glycoprotein (IVW: P=1.39×10-2, OR=0.81, 95%CI: 0.69-0.96) and the levels of Delta and Notch-like epidermal growth factor-related receptor (IVW: P=3.7×10-2, OR=0.73, 95%CI: 0.55-0.98) were positive, indicating that the results remained significant after excluding the effects of other circulating inflammatory proteins that had an impact on myocardial hypertrophy. (3) In colocalization, T-cell surface glycoprotein CD6 isoform levels had H3+H4=0.96, with the most significant single nucleotide polymorphism being rs59570070, suggesting an intrinsic link between T-cell surface glycoprotein CD6 isoform levels and myocardial hypertrophy. (4) Sensitivity results showed no abnormalities, indicating no heterogeneity or pleiotropic effects influencing the results. (5) These results verified that T cell surface glycoprotein CD6 isoforms, Slit chemokine, Delta and Notch-like epidermal growth factor-related receptors, interleukin-2, and sulfotransferase 1A1 had a unidirectional causal effect on myocardial hypertrophy. T cell surface glycoprotein CD6 isoforms and Delta and Notch-like epidermal growth factor-related receptors had the deepest impact, suggesting that there may be related pathways between T cell surface glycoprotein CD6 isoforms and myocardial hypertrophy. Mendelian randomization studies require large amounts of clinical data and therefore often use European samples from international databases for analysis. Since this analytical method has significant advantages in causal inference, precision medicine, and cross-population validation, its research results still hold great significance for the medical development in China. As Mendelian randomization research deepens, it also promotes the collection and analysis of clinical data in China to some extent. In the future, we can further analyze key protein mechanisms, combine multiomics and clinical validation, develop an inflammatory marker monitoring system and novel anti-inflammatory therapies, thereby promoting the prevention and control of cardiovascular diseases and the development of personalized medicine.

Key words: myocardial hypertrophy,  circulating protein, cardiovascular disease, mendelian randomization, causal relationship, observational study, co-localization, multivariate Mendelian randomization

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