Jia Ming-Jie, Yin Hua-Fang, Liang Ying-Chao, Jiang Feng, Li Hui-Lin
The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, Guangdong, China.
Front Immunol. 2025 Jan 20;15:1462815. doi: 10.3389/fimmu.2024.1462815. eCollection 2024.
Numerous clinical studies have observed a close relationship between serum trace elements, nutrients, and autoimmune diseases. However, whether there is a genetic causal effect between serum trace elements, nutrients, and autoimmune diseases remains unclear.
This study aims to investigate the causal effects of serum trace elements and nutrients on 21 autoimmune diseases using Mendelian randomization (MR).
Single nucleotide polymorphisms for the exposure factors (serum trace elements and vitamins) were obtained from the published UK Biobank database and genome-wide association study (GWAS) public databases. Outcome GWAS data were derived from the FinnGen database. MR was employed to explore the causal relationships between 9 trace elements and 6 vitamins and autoimmune diseases. Causal inference was performed using inverse variance weighted methods, MR Egger, and weighted median methods. Subsequently, heterogeneity tests, horizontal pleiotropy tests, MR-PRESSO tests, and leave-one-out analyses were conducted for sensitivity analysis to evaluate the robustness of the study results. Finally, trace elements and vitamins that were statistically significant in the IVW method and had consistent effect sizes and odds ratios across five methods were selected as exposure factors with a causal relationship to diabetes and its complications. Additionally, multivariable Mendelian randomization was employed to assess the combined effects of multiple exposure factors on autoimmune diseases.
MR analysis indicated that elevated levels of the trace element copper were associated with an increased risk of systemic lupus erythematosus (SLE) and a decreased risk of ulcerative colitis. Carotene was found to have a negative causal relationship with adult-onset Stills disease (AOSD). Elevated levels of copper and selenium were associated with an increased risk of autoimmune hyperthyroidism. Calcium levels showed a negative causal relationship with the risk of polyarteritis nodosa. MVMR results demonstrated that selenium could independently affect the risk of autoimmune hyperthyroidism, separate from copper.
The findings from both univariable and multivariable Mendelian randomization studies support a causal relationship between trace elements, nutrients, and autoimmune diseases. These results have significant clinical implications for developing targeted prevention and treatment strategies for autoimmune diseases.
众多临床研究观察到血清微量元素、营养素与自身免疫性疾病之间存在密切关系。然而，血清微量元素、营养素与自身免疫性疾病之间是否存在遗传因果效应仍不清楚。
本研究旨在利用孟德尔随机化（MR）研究血清微量元素和营养素对21种自身免疫性疾病的因果效应。
从已发表的英国生物银行数据库和全基因组关联研究（GWAS）公共数据库中获取暴露因素（血清微量元素和维生素）的单核苷酸多态性。结局GWAS数据来自芬兰基因数据库。采用MR探索9种微量元素和6种维生素与自身免疫性疾病之间的因果关系。使用逆方差加权法、MR-Egger法和加权中位数法进行因果推断。随后，进行异质性检验、水平多效性检验、MR-PRESSO检验和留一法分析进行敏感性分析，以评估研究结果的稳健性。最后，选择在逆方差加权法中具有统计学意义且在五种方法中效应大小和比值比一致的微量元素和维生素作为与糖尿病及其并发症存在因果关系的暴露因素。此外，采用多变量孟德尔随机化评估多个暴露因素对自身免疫性疾病的综合影响。
MR分析表明，微量元素铜水平升高与系统性红斑狼疮（SLE）风险增加及溃疡性结肠炎风险降低相关。发现胡萝卜素与成人斯蒂尔病（AOSD）存在负因果关系。铜和硒水平升高与自身免疫性甲状腺功能亢进风险增加相关。钙水平与结节性多动脉炎风险呈负因果关系。多变量孟德尔随机化结果表明，硒可独立于铜影响自身免疫性甲状腺功能亢进风险。
单变量和多变量孟德尔随机化研究结果均支持微量元素、营养素与自身免疫性疾病之间存在因果关系。这些结果对制定自身免疫性疾病的针对性预防和治疗策略具有重要临床意义。
