Zhong Chuanqi, Duan Chaoying, Zeng Yuan, Guo Tianhong
Clinical Laboratory, Luzhou Maternal and Child Health Hospital (Luzhou Second People's Hospital), Luzhou, Sichuan Province, China.
Clinical Laboratory, Deyang Second People's Hospital, Deyang, Sichuan Province, China.
Medicine (Baltimore). 2025 Aug 22;104(34):e44033. doi: 10.1097/MD.0000000000044033.
Diabetes is a prevalent global metabolic and endocrine disorder that is associated with a high incidence of complications and organ system dysfunction. Bone marrow (BM) as a previously neglected site of diabetic end-organ damage, characterized by microangiopathy, neuropathy, fat deposition, and inflammation. As a result, diabetes may lead to negative consequences for physiologic hematopoiesis, which may increase the risk of aplastic anemia (AA). Summary genetic data for diabetes mellitus (DM) were sourced from FinnGen; while the data for AA and immune cell traits were obtained from the IEU Open GWAS database. We performed a two-sample univariable Mendelian randomization (MR) analysis to investigate the causal effects of DM on AA. Simultaneously, multivariable MR was utilized to further estimate the direct effect of subgroup (distinct types) of diabetes on AA. Then, a two-step mediation MR analysis was conducted to examine 731 immune cell traits that may mediate these effects. Several methods were used to evaluate the robustness of the results, including sensitivity analyses with Cochran Q statistic, MR-Egger and MR-PRESSO, which also help mitigate potential bias from horizontal pleiotropy. The two-sample univariate MR analysis demonstrated DM was significantly and positively linked to the incidence of AA (IVW, OR = 1.12; 95% CI: 1.05-1.95; P = 5.11e-04), which was comparable to the direct effect estimated for type 2 diabetes on AA risk in multivariable MR (multivariable IVW, OR = 1.18; 95% CI: 1.03-1.35; P = 1.96e-02). In two-step mediation MR, we explored 54 immune cell traits associated with DM, among these, only the Resting CD4 + regulatory T cell absolute count emerged as a potential mediator influencing the risk of AA, accounting for 10.64% of the effect. We found robust genetic evidence for a causal association between DM and AA risk, and rest CD4+ Treg absolute count, might mediate this effect. However, the potential implications of our findings for AA prevention require validation through well-powered randomized clinical trials.
糖尿病是一种普遍存在的全球代谢和内分泌紊乱疾病，与并发症和器官系统功能障碍的高发病率相关。骨髓（BM）作为糖尿病终末器官损伤先前被忽视的部位，其特征为微血管病变、神经病变、脂肪沉积和炎症。因此，糖尿病可能对生理性造血产生负面影响，这可能会增加再生障碍性贫血（AA）的风险。糖尿病（DM）的汇总遗传数据来自芬兰基因组计划（FinnGen）；而AA和免疫细胞特征的数据则从国际暴露组学联盟开放全基因组关联研究（IEU Open GWAS）数据库获得。我们进行了两样本单变量孟德尔随机化（MR）分析，以研究DM对AA的因果效应。同时，利用多变量MR进一步估计糖尿病亚组（不同类型）对AA的直接效应。然后，进行了两步中介MR分析，以检验731种可能介导这些效应的免疫细胞特征。使用了几种方法来评估结果的稳健性，包括使用 Cochr an Q统计量、MR-Egger和MR-PRESSO进行敏感性分析，这也有助于减轻水平多效性带来的潜在偏差。两样本单变量MR分析表明，DM与AA的发病率显著正相关（逆方差加权法，OR = 1.12；95%置信区间：1.05 - 1.95；P = 5.11×10⁻⁴），这与多变量MR中估计的2型糖尿病对AA风险的直接效应相当（多变量逆方差加权法，OR = 1.18；95%置信区间：1.03 - 1.35；P = 1.96×10⁻²）。在两步中介MR中，我们探索了54种与DM相关的免疫细胞特征，其中，只有静息CD4⁺调节性T细胞绝对计数作为影响AA风险的潜在中介因素出现，占该效应的10.64%。我们发现了DM与AA风险之间因果关联的有力遗传证据，静息CD4⁺调节性T细胞绝对计数可能介导了这种效应。然而，我们的研究结果对AA预防的潜在意义需要通过有充分效力的随机临床试验来验证。
