Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort.

OBJECTIVE: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. METHODS: A nested ALS case-control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma-mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. RESULTS: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1-15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08-3.87) and lead (OR = 1.89, 95% CI = 0.97-3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27-0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. INTERPRETATION: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a-n/a.

Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson disease.

OBJECTIVE: Inflammatory response plays an important role in Parkinson disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in 3 population-based case-control studies from Denmark and France. METHODS: We included 2,056 cases and 2,723 controls from 3 PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions. RESULTS: Both carrying rs660895-G (AG vs AA: odds ratio [OR] = 0.81; GG vs AA: OR = 0.56; p-trend = 0.003) and ever smoking (OR = 0.56, p < 0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter = 1.37, p = 0.005), and dominant (interaction parameter = 1.54, p = 0.001) genetic models without any heterogeneity (I² = 0.0%); the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR = 0.64, p < 0.001) disappeared among ever smokers (OR = 1.00, p = 0.99). Similar interactions were observed when we investigated light and heavy smokers separately. INTERPRETATION: Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. Ann Neurol 2017;82:655-664.

Association of Parkinson's disease with industry sectors: a French nationwide incidence study.

In order to identify working environments at risk for Parkinson's disease (PD), we investigated the relation between the importance of industry sectors, used as a surrogate for occupational exposures, and PD incidence in French cantons. The number of incident PD cases (2010-2014) in 3689 cantons of metropolitan France was determined using drug claims from French National Health Insurance databases. The proportions of workers in 38 industry sectors in 2006 were calculated for each canton. Associations between the proportions of workers in industry sectors and PD age/sex-standardized incidence ratios were examined using incidence rate ratios (IRR) and 95% confidence intervals (CI) estimated with multilevel negative binomial regressions with a random intercept at the canton-level and adjusted for smoking, deprivation index, and density of neurologists. We then used two-step semi-Bayes hierarchical regression (HR) to include prior information about exposure to pesticides, metals, and solvents in each industry sector. We identified 112,625 incident cases. PD incidence was higher in areas characterized by high proportions of workers in "Agriculture, forestry and fishing" (IRRHR = 1.042; CI 95% = 1.014-1.070; p-TrendHR = 0.004), "Manufacture of textiles, wearing apparel, leather and related products" (IRRHR = 1.024; CI 95% = 1.005-1.044; p-TrendHR = 0.010), and "Manufacture of basic metals and fabricated metal products, except machinery and equipment" (IRRHR = 1.024; CI 95% = 1.003-1.046; p-TrendHR = 0.071). This nationwide study, based on a comprehensive analysis of industry sectors, shows significant associations between high proportions of workers in specific industry sectors (agriculture, metallurgy, textile) and PD incidence that may be targeted in further epidemiological studies to replicate and better understand these associations.

Is the incidence of motor neuron disease higher in French military personnel?

Objective: Previous studies, mostly from the United States, showed an increased risk of motor neuron disease (MND) in military personnel. We compared MND incidence rates in French military personnel to that in the general population. Methods: Among persons covered between 2010 and 2016 by the Caisse Nationale Militaire de Sécurité Sociale (CNMSS, military personnel) and the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés (CNAMTS, general population) aged ≥50 years, we identified incident MND cases and estimated populations at risk using national health insurance databases. We estimated relative risks (RRs) and 95% confidence intervals (CIs) separately for men and women using age-adjusted Poisson regression. Analyses were also stratified by 10-year age groups. We used the E-value approach and probabilistic bias analysis to assess robustness of the results regarding unmeasured confounding by smoking. Results: On average, 25 cases/year were newly diagnosed with MND among military personnel aged ≥50 years. The incidence rate was higher for male military personnel compared to the general population (RR = 1.16; 95% CI = 1.05-1.29) but was similar for women (RR = 1.02; 95% CI = 0.79-1.31). Although there were no significant interactions with age and sex, the association was mainly explained by men aged 70-79 years. The prevalence of ever-smoking should be at least 1.1-fold higher in male CNMSS compared to male CNAMTS members to make the association in male military personnel not significant. Conclusion: MND incidence was 16% higher in French male military personnel, in agreement with studies from other countries. Smoking may contribute to this finding. Further studies are needed to identify exposures that drive this association.

Age-dependent sex ratios of motor neuron disease: French nationwide study and meta-analysis.

OBJECTIVE: To examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies. METHODS: We used data from the French National Health Insurance databases. Patients with incident MND (2010-2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression. Poisson, Gompertz, and multistep models were used to model the relation between age and incidence. We performed a meta-analysis (n = 28 studies) and used meta-regression to examine the relation of age with incidence rates and ratios. RESULTS: In France, we identified 10,848 patients with incident MND (6,021 men, 4,827 women). Incidence was higher in men than in women in all age groups. M/F ratios were significantly different across age groups and followed a quadratic trend (p < 0.001). Between 20 and 49 years, the average M/F ratio was 2.26 (95% confidence interval [CI] = 1.96-2.62); it was 1.41 (95% CI = 1.35-1.47) between 50 and 84 years, and 1.88 (95% CI = 1.64-2.17) after 85 years. Incidence was lower in women than men at younger ages, but increased more steeply in women than men. Similar patterns were observed in the meta-analysis of incidence studies, especially in 19 higher-quality studies. CONCLUSION: The relation between age and M/F incidence ratios of MND follows a quadratic U-shaped pattern with an abrupt drop after the fifth decade. The change in M/F ratios before and after menopause suggests that reproductive/hormonal protective factors have a role in women and should prompt further studies to explore this hypothesis.