We are conducting a case-control study of PD nested in the Agricultural Health Study (AHS). The parent AHS is a cohort study of 89,000 licensed pesticide applicators and their spouses, recruited in 1993-97 in Iowa and North Carolina, which was designed to evaluate the role of farming-related exposures in chronic disease. The PD study is called the Farming and Movement Evaluation (FAME) study;
its specific aims are to examine the relationship of PD to (i) pesticide exposure;(ii) other neurotoxicants, particularly metals;(iii) lifestyle factors including diet, smoking, and caffeine;(iv) skin melanin, to examine racial/ethnic differences;and (v) polymorphisms in genes involved in dopaminergic neurotransmission, xenobiotic metabolism, or xenobiotic-specific membrane transport. Field work for the case-control study is complete;we have enrolled 115 cases and 384 controls. Suspect cases were identified using information from the AHS, and the diagnosis of PD was verified by movement disorder specialists using an in-home neurologic exam, a videotaped movement evaluation, and medical records including response to medication. Controls were a random sample from the remaining cohort, frequency matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources: (i) interview information on pesticide use, other exposures, and lifestyle already collected in the AHS;(ii) blood samples to measure organochlorines and metals and for DNA banking, and samples of house and farm equipment dust to measure certain pesticides and metals;and (iii) new telephone interviews which obtained information on lifetime use of specific pesticides implicated in PD by case reports or animal research as well as exposure to other neurotoxicants. The FAME study exploits the unique opportunity provided by the AHS to study PD in an occupational group defined by pesticide use, combining rigorous methods of case-finding with several complementary methods of exposure assessment. Pesticide data from FAME are currently being analyzed, but several other analyses have been completed. We investigated the relationship of blood metal levels to PD by measuring whole blood metal levels in 99 confirmed PD cases and 116 matched controls using inductively coupled plasma-mass spectrometry. For cases, the mean time between diagnosis and blood collection was 7.4 years. Seven of ten elements analyzed were detected in almost all subjects (copper, iron, lead, magnesium, manganese, selenium, and zinc). While we saw expected associations of metals with known predictors (eg, lead and smoking, lead and age), we observed no differences in blood metal levels between cases and controls, nor did we find differences related to time since diagnosis among cases. The half-life of metals in blood is relatively short, and the latency between metal exposure and disease may be long. Thus measuring current blood levels may not reflect the etiologically relevant time-window. In several recent analyses, we have evaluated the role of genetic susceptibility in PD. One analysis evaluated common polymorphic variants in SNCA, the gene for synuclein, a protein important in some cases of familial PD. Genetic variability in SNCA has been inconsistently associated with sporadic PD risk. Changes in SNCA expression have been reported for some variants, but the role of SNCA as a susceptibility factor in PD is inconclusive. We evaluated 61 SNCA variants in FAME. Variants were selected based on prior association, population frequency, and mechanistic hypotheses. Allelic associations were assessed with Fishers exact test;2- and 3-marker haplotypes were also tested. We genotyped 100 cases and 370 controls. Three SNPs deviating from HWE and with poor call rates were excluded from analysis. Four SNPs were mono-allelic. Call rates were >0.98 for all others. Seven SNPs were associated with PD risk (P<0.10), three directlyand four inversely. Haplotypic analyses did not identify stronger associations. We conclude that common SNCA SNPs are associated with PD, although none was significant after Bonferroni correction. Our observations replicate prior reports for rs356186, rs3822086, rs2737026, and rs2736994. Other associations are either novel or conflict with prior reports. These results further support SNCA as a susceptibility locus for PD, but suggest significant population heterogeneity or environmental interaction. Another analysis combined data from FAME and PEAK, an incident case-control study based in a California HMO, to evaluate the role of the organic cation transporter (OCT2) gene (SLC22A2) in PD risk. OCT2, a membrane transporter with affinity for small cations including MPP+ and dopamine, is preferentially expressed in kidney, choroid plexus, olfactory mucosa and substantia nigra pars compacta dopaminergic neurons, where it may play a role in cell integrity. The A270S (rs316019) and A1506G (rs316003) variants were genotyped in FAME and PEAK. A total of 694 PD cases and 1007 controls were studied. Results for the two studies were similar. In combined analyses, both variants were inversely associated with PD. In allelic analyses, the OR for the A270S variant was 0.76 (95%CI: 0.58,0.99, p=0.043) and for the A1506 variant was 0.69 (95%CI: 0.58,0.82, p<0.001). In genotypic analyses, the association was stronger with two compared to one copy of the variant, and tests for trend were significant (p=0.047 and p<0.001, respectively). We conclude that these two variants of the OCT2 membrane transporter are inversely associated with PD risk, suggesting a role for OCT2 in the pathogenesis of PD. Two other genetic analyses used data from a consortium of five North American case-control studies. The dopamine receptor D2 (DRD2) and D3 (DRD3) genes are associated with both PD risk and nicotine dependence. In an analysis including 1325 PD cases and 1735 age- and sex-matched controls, we evaluated whether polymorphisms in these genes were associated with PD risk or modified the inverse association of smoking with PD. Six DRD2 and two DRD3 polymorphisms were genotyped in a common laboratory. Smoking data were collected with a structured interview. Among white non-Hispanics, homozygous carriers of the Taq1A DRD2 variant had increased PD risk compared to wildtype homozygotes (OR=1.5, 95% CI 1.0-2.3). In contrast, there was an inverse association of PD risk with the Taq1A variant in African Americans. Among white Hispanics who carried two alleles, the Ser9Gly DRD3 variant was associated with a decreased risk of PD (OR=0.4, 95%CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. In animal models of PD, caffeine renders neuroprotection by blocking the adenosine receptor A2A (ADORA2A). Cytochrome P450 1A2 (CYP1A2) is the primary pathway of caffeine metabolism. In an analysis including 1325 PD cases and 1735 age- and sex-matched controls, we evaluated whether ADORA2A and CYP1A2 polymorphisms were associated with PD risk or modified the inverse association of caffeine with PD. Information on caffeine intake was collected by structured interview. Four ADORA2A and four CYP1A2 polymorphisms were genotyped in a common laboratory. Two ADORA2A polymorphisms were inversely associated with PD risk ss993074955, a 5 variant (allelic OR= 0.51, 95% CI 0.33-0.80) and rs5996696, a promoter region variant (OR for AC and CC genotypes compared with the AA genotype was 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively). The other ADORA2A and CYP1A2 polymorphisms were not associated with PD risk. There was no genotype X caffeine interaction for ADORA2A polymorphisms. For CYP1A2 SNPs, the caffeine-PD association was strongest among subjects homozygous for variant allele for rs762551 and rs2470890 (p for interaction <0.10).

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2010
Total Cost
$136,587
Indirect Cost
City
State
Country
Zip Code
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

Showing the most recent 10 out of 20 publications