Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disorder which selectively damages upper and lower motor neurons
When leave-one-out sensitivity analysis was performed, the change of inverse variance weighted (IVW) point estimate was detected for vitamin C when omitting rs2559850, but not for vitamin B12 (Supplementary Figure S3)
The results further supported that there was no causal relationship between vitamin C as well as vitamin B12 and ALS risk (Figure 2)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disorder which selectively damages upper and lower motor neurons (van Es et al, 2017). It is typically characterized by progressive motor deficits such as dysphagia, dysarthria, muscle atrophy and weakness of the trunk and extremities, and even respiratory failure (Masrori and Van Damme, 2020). Due to severe clinical symptoms and huge socio-economic burden, an increasing number of Circulating Micronutrients and ALS Risk studies have been implemented to investigate the predisposition factors of ALS and explore its possible pathogenesis. A center-based survey including 202 ALS patients and 208 healthy controls showed that lower circulating levels of vitamin C and higher levels of retinol were significantly related to an increased risk of ALS (Wang et al, 2020). Due to the small sample size, inevitable potential confounding factors and reverse causation, the results from the observational studies mentioned above are inconsistent
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