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[Preprint]. 2024 Feb 28:2024.02.27.24303143.
doi: 10.1101/2024.02.27.24303143.

Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study

Dae Gyu Jang  1   2 , John Dou  3 , Emily J Koubek  1   2 , Samuel Teener  1   2 , Lili Zhao  4 , Kelly M Bakulski  3 , Bhramar Mukherjee  5 , Stuart A Batterman  6 , Eva L Feldman  1   2 , Stephen A Goutman  1   2
Affiliations

Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study

Dae Gyu Jang et al. medRxiv. .

Update in

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. 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.

Results: 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, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, 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 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.

Keywords: Amyotrophic lateral sclerosis (ALS); environmental risk score; metals; polygenic risk score.

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Conflict of interest statement

Competing Interests DGJ: None. JD: None. EJK: None. ST: None. LZ: None. KMB: None. BM: None. SAB: None. 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.

Figures

Figure 1.
Figure 1.. Study overview.
(A) Participants with (n=454) or without (n=294) amyotrophic lateral sclerosis (ALS) provided blood and/or urine samples. Polygenic risk scores (PGS) for ALS risk or genes related to metal metabolism were available for a subset of participants. (B) Blood and urine samples were collected from study participants and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to measure the concentrations of various metals. After removing metals in which over 40% of the samples fell under the limit of detection (LOD), the statistical weight of each metal was determined, and overall environmental risk scores (ERS) were calculated. Individual ERS for plasma and urine samples were developed for risk (plasma, ERSPR; urine, ERSUR) and survival (plasma, ERSPS; urine, ERSUS). These scores represent the cumulative exposure to various metals and serve as a comprehensive indicator of environmental risk. Image created using BioRender.com.
Figure 2.
Figure 2.. Plasma single metal and mixture associations with ALS risk.
Single metal logistic regression models based on plasma samples where the outcome is case/control status, the predictors are log-transformed, standardized metal levels, and the covariates are continuous age at sample collection, sex, and military service. Mixture metal ERSPR (plasma risk environmental risk score). %BDL, percentage of samples below detection limit; ALS, amyotrophic lateral sclerosis; BH, Benjamini-Hochberg, red font are significant correlations; CI, confidence interval; OR, odds ratio corresponding to one standard deviation increase in log-transformed metals.
Figure 3.
Figure 3.. Urine single metal and mixture associations with ALS risk.
Single metal logistic regression models based on urine samples where the outcome is case/control status, the predictors are log-transformed, standardized metal levels, and the covariates are continuous age at sample, sex, military service. Mixture metal ERSUR (urine risk environmental risk score). %BDL, the percentage of samples below detection limit; CI, confidence interval; ALS, amyotrophic lateral sclerosis; BH, Benjamini-Hochberg, red font are significant correlations; OR, odds ratio corresponding to one standard deviation increase in log-transformed metals.
Figure 4.
Figure 4.. Cohort survival analysis based on plasma samples.
Cox proportional hazards survival models from plasma samples with the outcome of survival time since diagnosis (in years), the predictors are log-transformed, standardized metal levels, and adjustment covariates are age at diagnosis, sex, family history of ALS, onset segment, El Escorial criteria, and time between symptom onset and diagnosis. %BDL, the percentage of samples below detection limit; BH, Benjamini-Hochberg, red font are significant correlations; CI, confidence interval; ERSPS, plasma survival environmental risk score; HR, hazards ratio corresponding to one standard deviation increase in log-transformed metals.
Figure 5.
Figure 5.. Adjusted survival curves stratified by environmental risk score (ERS) quartile.
Kaplan-Meier survival curves of ERS quartiles adjusted for covariates with the inverse probability weights method for (A) plasma (ERSPS) and (B) urine (ERSUS) sample sets. Adjusted covariates are age at sample collection, sex, military service, and family history of ALS. Dashed lines indicate the median survival in each ERS strata. The estimated adjusted median survival times for plasma (A) are 3.56 years for Quartile 1 (Q1), 2.43 years for Quartile 2 (Q2), 2.35 years for Quartile 3 (Q3), and 1.85 years for Quartile 4 (Q4). Estimated adjusted median survival times for urine (B) are 3.25 years for Q1, 2.62 years for Q2, 2.29 years for Q3, and 1.92 years for Q4. Adjusted survival curves and adjusted median survival time estimates are pooled across all 20 imputed datasets.
Figure 5.
Figure 5.. Adjusted survival curves stratified by environmental risk score (ERS) quartile.
Kaplan-Meier survival curves of ERS quartiles adjusted for covariates with the inverse probability weights method for (A) plasma (ERSPS) and (B) urine (ERSUS) sample sets. Adjusted covariates are age at sample collection, sex, military service, and family history of ALS. Dashed lines indicate the median survival in each ERS strata. The estimated adjusted median survival times for plasma (A) are 3.56 years for Quartile 1 (Q1), 2.43 years for Quartile 2 (Q2), 2.35 years for Quartile 3 (Q3), and 1.85 years for Quartile 4 (Q4). Estimated adjusted median survival times for urine (B) are 3.25 years for Q1, 2.62 years for Q2, 2.29 years for Q3, and 1.92 years for Q4. Adjusted survival curves and adjusted median survival time estimates are pooled across all 20 imputed datasets.
Figure 6.
Figure 6.. Cohort survival analysis based on urine samples.
Cox proportional hazards survival models from urine samples with the outcome of survival time since diagnosis (in years), the predictors are log-transformed, standardized metal levels, and adjustment covariates are age at diagnosis, sex, family history of amyotrophic lateral sclerosis (ALS), onset segment, El Escorial criteria, and time between symptom onset and diagnosis. %BDL, the percentage of samples below detection limit; BH, Benjamini-Hochberg, red font are significant correlations; CI, confidence interval; ERSUS, urine survival environmental risk score; HR, hazards ratio corresponding to one standard deviation increase in log-transformed metals.
Figure 7.
Figure 7.. Distribution of environmental risk scores (ERS) by high and low occupational metal exposure.
Distribution of the environmental risk scores (ERS) for (A) plasma (ERSPR) and (B) urine (ERSUR) by high (plasma, n=99; urine, n=51) and low (plasma, n=292; urine, n=265) occupational metal exposure groups. The high metal exposure group is defined by Standard Occupational Classification (SOC) codes “Building and Grounds Cleaning and Maintenance” (SOC 37), “Construction and Extraction” (SOC 47), “Installation, Maintenance, and Repair” (SOC 49), and “Production Occupations” (SOC 51). All other occupations are included in the low metal exposure group. P<0.05 by Wilcoxon test.
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