Anhui University of Chinese Medicine, Hefei 230038, China.
Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100089, China.
J Trace Elem Med Biol. 2024 Jul;84:127430. doi: 10.1016/j.jtemb.2024.127430. Epub 2024 Mar 11.
Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence.
We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors.
By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to -0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179-0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to -0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test.
Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.
帕金森病（PD）是一种中枢神经系统退行性疾病，其具体病因仍不清楚。目前，人们认为主要的病理基础是大脑纹状体中多巴胺浓度的降低。尽管许多先前的研究认为铁作为一种重要的营养元素参与了 PD 的发生和发展，但铁稳态指标中的总铁结合能力（TIBC）、转铁饱和度（TSAT）、铁蛋白和血清铁与 PD 之间是否存在因果关系，缺乏有效的遗传证据。
我们使用孟德尔随机化（MR）作为分析方法，基于迄今为止最大的全基因组关联研究（GWAS）数据，有效评估暴露与结局之间的遗传关联。通过使用不受任何因果关系影响的随机分配遗传工具变量（SNPs，单核苷酸多态性），我们在控制混杂因素的同时，有效评估了铁稳态标志物与 PD 之间的因果关系。
通过对与铁稳态标志物相关的 86 个 SNP 和与 PD 相关的 12,858,066 个 SNP 的协调分析，最终筛选出 56 个与 PD 相关的铁稳态全基因组显著相关的 SNP。逆方差加权（IVW）分析结果表明，铁（β=-0.524；95%Cl=-0.046 至 -0.002；P=0.032）被认为与 PD 存在遗传因果关系。Cochran's Q、Egger 截距和 MR-PRESSO 全局检验未检测到异质性和多效性（P>0.05）。Mr Steiger 方向性检验进一步证实了我们对铁和 PD 潜在因果方向的估计（P=0.001）。此外，TIBC（β=-0.142；95%Cl=-0.197-0.481；P=0.414）、TSAT（β=-0.316；95%Cl=-0.861-0.229；P=0.255）和铁蛋白（β=-0.387；95%Cl=-1.179-0.405；P=0.338）与 PD 没有遗传因果关系，且结果无异质性和多效性（P>0.05）。此外，TIBC（β=-0.142；95%Cl=-0.197-0.481；P=0.414）、TSAT（β=-0.316；95%Cl=-0.861-0.229；P=0.255）和铁蛋白（β=-0.101；95%Cl=-0.987 至 -0.405；P=0.823）与 PD 没有遗传因果关系，且结果无异质性和多效性（P>0.05）。TIBC（P=0.008）、TSAT（P=0.000）和铁蛋白（P=0.013）均与 MR Steiger 直接性检验的估计结果一致。
本研究发现，在四种铁稳态标志物中，血清铁与 PD 之间存在遗传因果关系，血清铁水平与 PD 风险呈负相关。此外，TIBC、TSAT、铁蛋白与 PD 无遗传因果关系。
