Farming and Movement Evaluation Study (FAME) FAME is a case-control study of PD nested in the Agricultural Health Study (AHS), including 115 PD cases and 384 controls. PD diagnosis was verified by movement disorder specialists. Controls were a random sample from the remaining cohort, matched to cases by age, sex, and state. Exposure was evaluated using data from the AHS and from additional telephone interviews. Pesticides and PD: Pathophysiologic mechanisms implicated in PD by experimental models and genetic studies include oxidative stress and mitochondrial dysfunction;certain pesticides may affect these mechanisms. We found that PD was associated with a group of pesticides that inhibit mitochondrial complex I (OR 1.7, 95% CI, 1.0-2.8), including rotenone (2.5, 1.3-4.7), and with a group of pesticides that cause oxidative stress (2.0, 1.23.6), including paraquat (2.5, 1.4-4.7). This is the first study to show an association of PD with rotenone and extends previous work on PD and paraquat with more detailed data, showing for example a dose-response. Our finding that PD was positively associated with pesticide groups defined by mechanisms previously implicated experimentally supports a role for these mechanisms in PD pathophysiology. Paraquat, glutathione transferases, and PD: Paraquat is one of the most widely used herbicides worldwide. It produces a PD model in rodents through redox cycling and oxidative stress and is associated with PD risk in humans. Glutathione transferases provide cellular protection against oxidative stress and could modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione-S-transferase M1 (GSTM1) or T1 (GSTT1). There was no interaction of paraquat with GSTM1. In contrast, GSTT1 genotype significantly modified the association of paraquat with PD (p-interaction=0.027). In men with functional GSTT1, the OR for paraquat was 1.5 (95% CI 0.6-3.6), while in men with homozygous GSTT1 deletion, the OR was 11.1 (95% CI 3.0-44.6). The GSTT1 deletion is common and might identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat. Dietary fat, pesticide exposure, and PD: Dietary fat intake may modify PD risk directly or by altering the response to environmental neurotoxicants including pesticides. We evaluated diet and pesticide use 10 years before diagnosis in 89 cases or a corresponding date in 336 frequency-matched controls. PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4, 95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor alpha-linolenic acid (0.4, 0.2-0.8). Moreover, associations of PD with paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake (p-interaction=0.02). Thus, high PUFA intake, which may mitigate neuroinflammation, moderated the PD risk associated with paraquat. In contrast, high saturated fat intake, which may increase oxidative stress, increased PD risk associated with rotenone. Alpha-synuclein, head injury, and PD: Sporadic PD is associated with both head injury and SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding alpha-synuclein. We evaluated the hypothesis that SNCA Rep1 modifies the association between head injury and PD risk in sporadic cases. Consistent with prior reports, short Rep1 genotype was associated with reduced PD risk and long Rep1 with increased risk, relative to medium-length Rep1. Head injury was not significantly associated with PD overall (OR 1.3, 95% CI 0.9-1.8), nor among those with short or medium-length Rep1. However, head injury was strongly associated with PD in those with long Rep1 (3.5, 1.4-9.2, p-interaction=0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p=0.03). While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of alpha-synuclein are high, as in those with Rep1 expansion. Peptidoglycan recognition proteins (PGRPs) and PD: Increased gut permeability, inflammation, and colonic alpha-synuclein pathology are present in early PD and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. PGRPs maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that PGRP genetic variants are associated with PD risk. We genotyped 30 SNPs in the four PGLYRP genes. Three of seven PGLYRP2 SNPs, one of five PGLYRP3 SNPs, and six of nine PGLYRP4 SNPs were significantly associated with PD risk. Association was strongest for PGLYRP4 5untranslated region SNP rs10888557 (GG reference, CG OR 0.6 95%CI 0.4-0.9, CC OR 0.15 95%CI 0.04-0.6;log-additive P-trend, 0.0004). These results are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. Personal protective equipment: Protective gloves and workplace hygiene can reduce pesticide exposure. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire in 69 PD cases and 237 controls. We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with ≥5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used ≥2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 95% CI 1.3, 11.7, interaction p=0.15;permethrin OR 4.3 95% CI 1.2, 15.6 interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among people who used <2 hygiene practices (OR 5.5 95% CI 1.1, 27.1) but not among people who used 2 or more practices (interaction p=0.02). Thus protective glove use and hygiene practices were important modifiers of the association between pesticides and PD, and may reduce risk of PD associated with certain pesticides. Swedish National Registers I have collaborated with Fang Fang, Karin Wirdefeldt, and Honglei Chen on studies of PD using data from the Swedish National Registers. PD and cancer: In order to compare cancer occurrence in individuals with and without PD, and between siblings of these individuals, we conducted a family-based matched cohort. We assessed risk of incident cancer in PD patients (N=11,786) versus a matched cohort of PD free individuals (N=58,930) and in siblings of PD patients (N=16,841) versus siblings of PD free individuals (N=84,205). Cancer occurrence was slightly higher in PD patients than in PD free individuals (HR=1.05, 95% CI: 1.00, 1.10), largely due to cancers within 1 year before and after index date for PD, but risk for smoking-related cancers was lower (HR = 0.87, 95% CI: 0.79, 0.96). PD patients had higher risk of melanoma both until 1 year before index date (HR = 1.53, 95% CI: 1.23, 1.91) and after 1 year since index date (HR=1.46, 95% CI: 1.01, 2.10). In the sibling comparison, cancer occurrence was largely similar. These results indicate that occurrence of melanoma is higher among PD patients and that mechanisms other than familial explain the association.
| Goldman, S M; Umbach, D M; Kamel, F et al. (2015) Head injury, ?-synuclein Rep1 and Parkinson's disease: a meta-analytic view of gene-environment interaction. Eur J Neurol 22:e75 |
| Furlong, Melissa; Tanner, Caroline M; Goldman, Samuel M et al. (2015) Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease. Environ Int 75:144-50 |
| Kirrane, Ellen F; Bowman, Christal; Davis, J Allen et al. (2015) Associations of Ozone and PM2.5 Concentrations With Parkinson's Disease Among Participants in the Agricultural Health Study. J Occup Environ Med 57:509-17 |
| Goldman, Samuel M; Kamel, Freya; Ross, G Webster et al. (2014) Peptidoglycan recognition protein genes and risk of Parkinson's disease. Mov Disord 29:1171-80 |
| Wirdefeldt, Karin; Weibull, Caroline E; Chen, Honglei et al. (2014) Parkinson's disease and cancer: A register-based family study. Am J Epidemiol 179:85-94 |
| Dong, Jing; Beard, John D; Umbach, David M et al. (2014) Dietary fat intake and risk for Parkinson's disease. Mov Disord 29:1623-30 |
| Kamel, Freya; Goldman, Samuel M; Umbach, David M et al. (2014) Dietary fat intake, pesticide use, and Parkinson's disease. Parkinsonism Relat Disord 20:82-7 |
| Chen, Honglei; Burton, Edward A; Ross, G Webster et al. (2013) Research on the Pre-Motor Symptoms of Parkinson's Disease: Clinical and Etiological Implications. Environ Health Perspect : |
| Kamel, Freya (2013) Epidemiology. Paths from pesticides to Parkinson's. Science 341:722-3 |
| Goldman, Samuel M; Kamel, Freya; Ross, G Webster et al. (2012) Head injury, ?-synuclein Rep1, and Parkinson's disease. Ann Neurol 71:40-8 |
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