Jang Dae Gyu, Dou John, Koubek Emily J, Teener Samuel, Zhao Lili, Bakulski Kelly M, Mukherjee Bhramar, Batterman Stuart A, Feldman Eva L, Goutman Stephen A
Department of Neurology, University of Michigan, Ann Arbor, MI.
NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI.
medRxiv. 2024 Feb 28:2024.02.27.24303143. doi: 10.1101/2024.02.27.24303143.
The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources.
Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs.
Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, <0.001; urine, OR=3.10, CI=2.43-3.97, <0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, <0.001; urine, HR=1.52, CI=1.31-1.76, <0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals.
Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.
肌萎缩侧索硬化症（ALS）的发病机制涉及遗传和环境因素。本研究调查血浆和尿液中的金属指标、ALS风险与生存以及暴露源之间的关联。
来自密歇根州的患有和未患有ALS的参与者提供血浆和尿液样本，通过电感耦合等离子体质谱法进行金属测量。使用风险和生存模型计算每种金属的比值比和风险比。创建环境风险评分（ERS）以评估暴露混合物与ALS风险、生存及暴露源之间的关联。ALS（ALS-PGS）和金属（金属-PGS）多基因风险评分由独立的全基因组关联研究和相关文献选择的单核苷酸多态性构建而成。
分析了454名ALS患者和294名对照参与者的血浆和尿液样本。包括铜、硒和锌在内的个别金属水平升高与ALS风险和生存显著相关。代表金属混合物的ERS与ALS风险（血浆，比值比=2.95，置信区间=2.38-3.62，<0.001；尿液，比值比=3.10，置信区间=2.43-3.97，<0.001）和较差的ALS生存（血浆，风险比=1.42，置信区间=1.24-1.63，<0.001；尿液，风险比=1.52，置信区间=1.31-1.76，<0.001）密切相关。添加ALS-PGS或金属-PGS并未改变金属与ALS风险和生存之间的显著性。具有高金属暴露潜力的职业与ERS升高相关。此外，职业和非职业性金属暴露与测量的血浆和尿液金属相关。
血浆和尿液中的金属与ALS风险增加和生存降低相关，与遗传风险无关，且与职业和非职业性金属暴露相关。这些数据强调了金属暴露在ALS风险和进展中的重要性。
