Li Yutong, Song Xingyu, Huang Yuyang, Zhou Sifan, Zhong Linkun
The First School of Clinical Medicine, Guangdong Medical University, Zhanjiang, 524023, Guangdong Province, China.
The Department of General Surgery, Zhongshan City People's Hospital, Zhongshan, 528400, Guangdong Province, China.
Sci Rep. 2025 Jan 8;15(1):1377. doi: 10.1038/s41598-025-85664-1.
Mendelian randomization (MR) was employed to investigate the causal relationships between immune cell phenotypes, hyperthyroidism (HD), and potential metabolic mediators. In this study, we acquired 731 immune cell phenotypes from genome-wide association studies (GWAS) (n = 18,622), HD data from the research by Handan Melike Dönertaş et al. (3,731 cases, 480,867 controls), and aggregated statistics of 1,400 blood metabolites from UK Biobank (n = 115,078). Bidirectional MR analysis was performed to explore the causal relationships between the immune cell phenotypes and HD, and two-sample and multi-variable MR were conducted to identify the potential plasma metabolites mediating in HD. In addition, sensitivity analyses were used to evaluate robustness, heterogeneity, and horizontal pleiotropy of results. Single-cell transcriptome-based exploration of potential key molecule and mechanism by which plasma metabolites regulated the immune cell differentiation in HD pathogenesis. Co-localization analysis was using single-cell eQTL (sc-eQTL) data with key molecule to probe genetically shared effects. Two-sample MRshowed that CD25 on naive-mature B cell, CD8 + NKT cell, and thymol sulfate level were found to have causal relationships with HD (P < 0.008). The causal relationship between thymol sulfate and HD were further validated in an independent cohort using the inverse-variance weighted (IVW). In addition, CD25 on naive-mature B cells and CD8 + NKT cells were both negatively correlated with thymol sulfate (P < 0.05). The results remained significant after MR-Egger and MR-PRESSO correction for horizontal pleiotropy and heterogeneity (P > 0.05). Multi-variable MR results showed that CD25 on naive-mature B cell and CD8 + NKT cell mediated 8.67% and 10.4% of the associations between thymol sulfate and HD, respectively. Moreover, thymol sulfate mediated the evolution of CD8 + NKT cells in the immune microenvironment, identifying PTPRC, PTK2B, KDM5A and TIGIT as the key participating molecules. Co-localization analysis showed that the key molecules had significant genetic sharing effects with CD8 + NKT cells (PPH4 > 0.75, R > 0.8, P < 0.05), with PTK2B having the broadest sharing interval. Current MR study provides evidence supporting causal relationships between several specific immune cell phenotypes and HD, as well as potential mediating metabolites. Thymol sulfate may increases the risk of HD pathogenesis by mediating the evolution of PTK2B genetic variants inducing CD8 + NKT cells in the progression of the immune microenvironment.
采用孟德尔随机化（MR）方法研究免疫细胞表型、甲状腺功能亢进症（HD）和潜在代谢介质之间的因果关系。在本研究中，我们从全基因组关联研究（GWAS）中获取了731种免疫细胞表型（n = 18,622），从Handan Melike Dönertaş等人的研究中获取了HD数据（3731例病例，480,867例对照），并从英国生物银行获取了1400种血液代谢物的汇总统计数据（n = 115,078）。进行双向MR分析以探索免疫细胞表型与HD之间的因果关系，并进行双样本和多变量MR以确定介导HD的潜在血浆代谢物。此外，使用敏感性分析来评估结果的稳健性、异质性和水平多效性。基于单细胞转录组探索血浆代谢物在HD发病机制中调节免疫细胞分化的潜在关键分子和机制。使用单细胞eQTL（sc-eQTL）数据与关键分子进行共定位分析，以探究基因共享效应。双样本MR显示，幼稚成熟B细胞、CD8 + NKT细胞上的CD25以及硫酸百里酚水平与HD存在因果关系（P < 0.008）。使用逆方差加权（IVW）在独立队列中进一步验证了硫酸百里酚与HD之间的因果关系。此外，幼稚成熟B细胞和CD8 + NKT细胞上的CD25均与硫酸百里酚呈负相关（P < 0.05）。在对水平多效性和异质性进行MR-Egger和MR-PRESSO校正后，结果仍然显著（P > 0.05）。多变量MR结果显示，幼稚成熟B细胞和CD8 + NKT细胞上的CD25分别介导了硫酸百里酚与HD之间8.67%和10.4%的关联。此外，硫酸百里酚介导了免疫微环境中CD8 + NKT细胞的演变，确定PTPRC、PTK2B、KDM5A和TIGIT为关键参与分子。共定位分析表明，关键分子与CD8 + NKT细胞具有显著的基因共享效应（PPH4 > 0.75，R > 0.8，P < 0.05），其中PTK2B的共享区间最广。当前的MR研究提供了证据，支持几种特定免疫细胞表型与HD之间的因果关系以及潜在的介导代谢物。硫酸百里酚可能通过介导PTK2B基因变异的演变诱导免疫微环境进展中的CD8 + NKT细胞，从而增加HD发病的风险。
