We propose expanding our existing Parkinson's disease, Environment and Genes (PEG) study population to further investigate the contributions of specific agricultural pesticides alone and in combination with biologically relevant genes that increase susceptibility to Parkinson's disease (PD). With prior funding, we have already enrolled 363 movement disorder specialist-confirmed idiopathic PD patients and, by the end of 2010, have enrolled 910 population controls from a heavily pesticide exposed population in three rural counties of California's Central Valley. All PEG study participants provide a biologic sample, complete a risk factor interview that includes detailed pesticide/farm work exposure assessments, and provide lifetime residential and occupational addresses that are combined with California state mandated commercial pesticide use reports in our sophisticated geographic information system (GIS) computer model to estimate ambient pesticide exposure over time.
Our specific aims i n this application are (1) Establish the largest case-control study of well characterized incident Parkinson's disease in the US with unprecedented pesticide exposure assessment by recruiting 500 additional movement disorder specialist-confirmed incident cases of PD utilizing the California PD Registry - a unique and time-limited resource for PD research given that the financial situation of the state of California jeopardizes future state funding to continue this effort and the 2,600 patients already identified are aging and progressing rapidly with regard to disease state;(2) Create a novel, comprehensive tool to assess pesticide exposures by incorporating data on wind speed, direction, and atmospheric mixing heights, farm boundaries, and soil composition and groundwater flow;and expand and validate our existing GIS-based computer model of pesticide exposure by incorporating occupational addresses, in addition to residential addresses, to estimate exposure to commercial pesticides and validating our model using Dept of Pesticide Regulation and CA Air Resource Board water and air measurements;and (3) Investigate novel gene-pesticide interactions for recognized PD risk genes (PARK1/PARK4 SNCA, PARK2 parkin, PARK5 UCHL1, PARK6 PINK, PARK8 LRRK2, and PARK13 HTRA2). While the PEG study has provided important and groundbreaking first results on pesticide and pesticide-gene interactions in PD in humans, this application provides the opportunity to increase our sample size and therefore our statistical power to evaluate the impact of less commonly used pesticides, combinations of pesticides, less frequent genetic mutations, and GxE interactions with one of the best pesticide exposure assessment models in a well defined and extensively phenotyped case population. Improving our understanding of environmental toxins, the genetic variation, and their impact on idiopathic PD will improve prevention efforts, advance therapeutic developments, and inform public policy on pesticide regulation.
Parkinson's disease (PD) is, after Alzheimer disease, the second most common brain disorder causing disability and loss of quality of life in more than 1% of all people over age 60 and costing the nation approximately 23 billion US Dollars annually. We do not know the causes of PD but research suggests that there are many, likely occurring over a long period of time, and probably requiring a combination of factors such as environmental exposure to toxins, genetic or hereditary factors, and gene-toxicants interactions during aging. By advancing our understanding of environmental toxins, genetic variation, and their impact on idiopathic PD scientific research can inform public policy on pesticide regulation, improve prevention efforts aimed at eliminating detrimental exposures, and advance therapeutic investigations.
|Kusters, Cynthia D J; Paul, Kimberly C; Guella, Ilaria et al. (2018) Dopamine receptors and BDNF-haplotypes predict dyskinesia in Parkinson's disease. Parkinsonism Relat Disord 47:39-44|
|Paul, Kimberly C; Jerrett, Michael; Ritz, Beate (2018) Type 2 Diabetes Mellitus and Alzheimer's Disease: Overlapping Biologic Mechanisms and Environmental Risk Factors. Curr Environ Health Rep 5:44-58|
|Paul, Kimberly C; Ling, Chenxiao; Lee, Anne et al. (2018) Cognitive decline, mortality, and organophosphorus exposure in aging Mexican Americans. Environ Res 160:132-139|
|Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2018) NFE2L2, PPARGC1?, and pesticides and Parkinson's disease risk and progression. Mech Ageing Dev 173:1-8|
|Paul, Kimberly C; Schulz, Jessica; Bronstein, Jeff M et al. (2018) Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurol 75:360-366|
|Chen, Honglei; Ritz, Beate (2018) The Search for Environmental Causes of Parkinson's Disease: Moving Forward. J Parkinsons Dis 8:S9-S17|
|Ritz, Beate R; Chatterjee, Nilanjan; Garcia-Closas, Montserrat et al. (2017) Lessons Learned From Past Gene-Environment Interaction Successes. Am J Epidemiol 186:778-786|
|Sanders, Laurie H; Paul, Kimberly C; Howlett, Evan H et al. (2017) Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk. Toxicol Sci 158:188-198|
|Mata, Ignacio F; Johnson, Catherine O; Leverenz, James B et al. (2017) Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease. Neurobiol Aging 56:211.e1-211.e7|
|Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2017) Organophosphate pesticides and PON1 L55M in Parkinson's disease progression. Environ Int 107:75-81|
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