Vasudevan Akshaya, Venkatesan Padmanaban
Department of Community Medicine, Christian Medical College, Vellore, Tamil Nadu, India; Affiliated to The Tamil Nadu Dr. MGR Medical University, Chennai, India.
Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India; Affiliated to The Tamil Nadu Dr. MGR Medical University, Chennai, India.
J Trace Elem Med Biol. 2025 Feb;87:127586. doi: 10.1016/j.jtemb.2024.127586. Epub 2024 Dec 27.
Observational studies have found that higher iron levels are associated with an increased risk of diabetes mellitus. Given the limitations of causal inferences from observational studies and the expensive and time-consuming nature of randomized controlled trials, Mendelian randomization analysis presents a reasonable alternative to study causal relationships. Previous MR analyses studying iron levels and diabetes have used indirect markers of iron levels, such as serum ferritin, and found conflicting results. In this study, we performed bidirectional Mendelian Randomization analyses using organ iron (liver, spleen, and pancreas) levels, which are more direct markers of iron status, to study the causal association of iron levels with type 2 diabetes mellitus and glycaemic traits.
Two sample MR analyses were employed bi-directionally to study the causal effect of liver, spleen, and pancreas iron levels on type 2 diabetes and glycaemic traits and the causal effect of type 2 diabetes on organ iron levels, using summary data from genome-wide association studies (UK-Biobank, DIAGRAM, and MAGIC consortia). SNPs associated with organ iron levels with a cut-off of P < 5 × 10 were used as instrumental variables for the MR analyses of the effect of organ iron levels on type 2 diabetes/glycaemic traits, and SNPs associated with diabetes mellitus with a cut-off of P < 5 × 10 were used as instrumental variables for the MR analyses of the causal effect of type 2 diabetes on organ iron levels. Serum ferritin (GWAS meta-analysis of deCODE, UK INTERVAL, and Denmark studies) and haemoglobin (Blood Cell consortium) were used as positive controls for the MR analysis with liver iron as the exposure. Primary analyses used the inverse variance weighted means of Wald's ratio. Sensitivity analyses included inverse variance weighted median, weighted mode, and MR-Egger methods.
Our findings reveal no causal association between liver and pancreas iron levels with type 2 diabetes (Liver iron: OR = 1.02, P = 0.1, Pancreas iron: OR = 1.11, P = 0.5). This also holds for glycaemic traits, except for the negative causal effect of liver iron levels on HbA1c (OR = 0.93, P = 0.001). Spleen iron levels had a negative causal effect on type 2 diabetes (OR = 0.94, P = 0.049). However, these exceptions are likely due to possible pleiotropy, as these associations can be explained by the effect of the genetic variants on factors that falsely decrease HbA1c levels. No causal association was found for the effect of type 2 diabetes on organ iron levels.
Organ iron levels, which are relatively more direct indicators of iron status, showed no causal association with type 2 diabetes in the European population.
观察性研究发现，铁水平升高与糖尿病风险增加有关。鉴于观察性研究因果推断的局限性以及随机对照试验成本高、耗时的特点，孟德尔随机化分析为研究因果关系提供了一种合理的替代方法。以往研究铁水平与糖尿病关系的孟德尔随机化分析使用的是铁水平的间接标志物，如血清铁蛋白，结果相互矛盾。在本研究中，我们使用器官铁（肝脏、脾脏和胰腺）水平进行双向孟德尔随机化分析，器官铁水平是铁状态更直接的标志物，以研究铁水平与2型糖尿病及血糖性状之间的因果关系。
使用全基因组关联研究（英国生物银行、DIAGRAM和MAGIC联盟）的汇总数据，采用双向两样本孟德尔随机化分析，研究肝脏、脾脏和胰腺铁水平对2型糖尿病和血糖性状的因果效应，以及2型糖尿病对器官铁水平的因果效应。与器官铁水平相关且P<5×10的单核苷酸多态性（SNPs）用作器官铁水平对2型糖尿病/血糖性状影响的孟德尔随机化分析的工具变量，与糖尿病相关且P<5×10的SNPs用作2型糖尿病对器官铁水平因果效应的孟德尔随机化分析的工具变量。血清铁蛋白（deCODE、英国INTERVAL和丹麦研究的全基因组关联研究荟萃分析）和血红蛋白（血细胞联盟）用作以肝脏铁为暴露因素的孟德尔随机化分析的阳性对照。主要分析采用Wald比的逆方差加权均值。敏感性分析包括逆方差加权中位数、加权模式和孟德尔-埃格方法。
我们的研究结果显示，肝脏和胰腺铁水平与2型糖尿病之间无因果关系（肝脏铁：比值比[OR]=1.02，P=0.1；胰腺铁：OR=1.11，P=0.5）。血糖性状方面也是如此，但肝脏铁水平对糖化血红蛋白（HbA1c）有负向因果效应（OR=0.93，P=0.001）。脾脏铁水平对2型糖尿病有负向因果效应（OR=0.94，P=0.049）。然而，这些例外情况可能是由于可能的多效性，因为这些关联可以通过基因变异对错误降低HbA1c水平的因素的影响来解释。未发现2型糖尿病对器官铁水平有因果关系。
器官铁水平是相对更直接的铁状态指标，在欧洲人群中与2型糖尿病无因果关系。
