“湿浊痰饮类病”理论整合转录组学与孟德尔随机化构建痰湿体质人群心力衰竭风险中的核心基因模型

Integrative transcriptomic and mendelian randomization analysis based on the theory of similar diseases and syndromes of damp-turbidity-phlegm-rheum to identify core genes associated with heart failure risk in individuals with phlegm-damp constitution

关键词:  湿浊痰饮类病  痰湿体质  心力衰竭  孟德尔随机化

Key words:  similar diseases and syndromes of damp-turbidity-phlegm-rheum  phlegm-damp constitution  heart failure  mendelian randomization

摘要:

[目的] 痰湿体质是中医经典体质之一，与代谢紊乱密切相关，国医大师张伯礼的“湿浊痰饮类病”理论指出痰湿体质是心力衰竭等重大慢性疾病的重要易感因素。然而，当前尚缺乏痰湿体质与心力衰竭之间遗传机制的系统研究。[方法] 研究基于“湿浊痰饮类病”理论，以“肥胖”与“高脂血症”作为痰湿体质的表征变量，利用全基因组关联研究（GWAS）数据，结合蛋白质数量性状位点（cis-pQTL）进行孟德尔随机化分析，筛选与痰湿体质相关的核心基因并构建痰湿体质心力衰竭风险基因模型，最后整合转录组学测序数据进行差异表达验证。[结果] 研究共识别出18个痰湿体质与心力衰竭风险相关的核心基因，其中羧肽酶Q（CPQ，P＜0.000 1）、凝血酶受体1（F2R，P＜0.000 1）、整合素αL亚基（ITGAL，P＜0.000 1）在心衰组织中呈显著上调表达，且与MR分析方向一致，具有较高的稳定性与解释力。[结论] 研究构建了中医痰湿体质与心力衰竭风险之间的遗传关联模型，为中医体质的现代化、量化研究提供了新路径，也为心衰的早期识别与精准干预提供了潜在靶点。

Abstract:

[Objective] Phlegm-damp constitution is one of the classical constitutional types in Traditional Chinese Medicine（TCM），closely associated with metabolic disorders. According to the theory of Similar Diseases and Syndromes of Damp-turbidity-phlegm-rheum proposed by the National Master of TCM，Professor Zhang Boli，the phlegm-damp constitution is considered a key susceptibility factor for chronic diseases such as heart failure. However，the genetic mechanisms linking phlegm-damp constitution and heart failure remain largely unexplored. [Methods] Guided by the aforementioned TCM theory，this study employed “obesity” and “hyperlipidemia” as representative phenotypes of phlegm-damp constitution. Genome-wide association study（GWAS） data were integrated with protein quantitative trait loci（cis-pQTL） information to perform Mendelian randomization（MR） analysis，identifying core genes associated with phlegm-damp constitution. A gene model for heart failure risk in phlegm-damp individuals was constructed，followed by validation using transcriptomic sequencing data to assess differential gene expression. [Results] A total of 18 core genes were identified as being associated with both phlegm-damp constitution and heart failure risk. Among them， CPQ （Carboxypeptidase Q）， F2R （Coagulation Factor II Receptor，also known as PAR1），and ITGAL（Integrin Subunit Alpha L） showed significantly upregulated expression in heart failure tissues and were consistent in direction with MR results，indicating high robustness and interpretability. [Conclusion] This study establishes a genetic association model between phlegm-damp constitution and heart failure risk，offering a novel approach for the modernization and quantification of TCM constitution theory. It also provides potential genetic targets for early detection and precision intervention in heart failure.