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Neuromuscular
Original research
Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study
  1. Dae-Gyu Jang1,2,
  2. John F Dou3,
  3. Emily J Koubek1,2,
  4. Samuel Teener1,2,
  5. Lili Zhou4,
  6. Kelly M Bakulski3,
  7. Bhramar Mukherjee5,
  8. Stuart A Batterman6,
  9. Eva L Feldman1,2,
  10. Stephen A Goutman1,2
  1. 1Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
  2. 2NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Department of Biostatistics, Corewell Health, Royal Oak, Michigan, USA
  5. 5Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
  6. 6Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Stephen A Goutman; sgoutman{at}med.umich.edu

Abstract

Background 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.

Methods Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs 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 single-nucleotide polymorphisms.

Results Plasma and urine samples from 454 ALS and 294 control participants were analysed. 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, p<0.001; urine, OR=3.10, CI=2.43–3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20–1.58, p<0.001; urine, HR=1.44, CI=1.23–1.67, p<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 were associated with measured plasma and urine metals.

Conclusion 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.

  • EPIDEMIOLOGY
  • ALS

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jnnp-2024-333978

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Contributors D-GJ, JFD, LZ, KMB, BM, SB, ELF and SAG conceived and designed the study. ST and SAG contributed to the acquisition of the data. D-GJ, JD and KMB performed the statistical analyses. D-GJ, EK and SAG interpreted the data, drafted the text and prepared the figures. All authors critically reviewed and approved the final version of the manuscript. SAG is the guarantor of the study.

    • Funding Funding was provided by the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS127188); National Institute of Environmental Health Sciences (NIEHS) (K23ES027221, R01ES030049); Centers for Disease Control and Prevention (R01TS000344); ALS Association (20-IIA-532, 20-PP-661); NeuroNetwork for Emerging Therapies; Peter R. Clark Fund for ALS Research; Robert and Katherine Jacobs Environmental Health Initiative; Richard Stravitz Foundation; Coleman Therapeutic Discovery Fund; Scott L. Pranger ALS Clinic Fund; the Dr. Randall W. Whitcomb Fund for ALS Genetics; University of Michigan. Metals analysis was carried out at the Dartmouth Trace Element Core Facility, which is supported by Dartmouth Cancer Center with NCI Cancer Center Support Grant 5P30 CA023108.

    • Competing interests ELF: Listed as inventors on a patent, Issue number US10660895, held by University of Michigan titled 'Methods for Treating Amyotrophic Lateral Sclerosis' that targets immune pathways for use in ALS therapeutics. SAG: Listed as inventors on a patent, Issue number US10660895, held by University of Michigan titled 'Methods for Treating Amyotrophic Lateral Sclerosis' that targets immune pathways for use in ALS therapeutics. Scientific consulting for Evidera.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.