Parkinson's disease (PD) occurrence is higher in rural than in urban populations of industrialized countries. Epidemiologic and human tissue studies suggested that pesticides may be responsible for causing dopaminergic cell death at increased rates. While many pathophysiologic pathways may be involved in the neurodegeneration responsible for PD, genetic factors are likely to determine a general susceptibility to neurodegeneration. There are a number of genetic polymorphisms of genes such as those coding for the cytochrome p450 super4amily of genes referred to as 'susceptibility genes'. However, they are generally not sufficient to cause disease unless a person encounters exposure to an environmental toxin: the disease is caused by a gene-environment interaction. Thus, it is imperative to assess genetic susceptibility in individuals exposed to a toxin. We will test the gene-environment interaction hypothesis by conducting an epidemiologic population-based case-control study of newly diagnosed PD patients from three rural California counties: Kern, Fresno, and Tulare. Over a four year period, we expect to collect 400 cases referred to us by local neurologists, farm worker clinics, and Parkinson's foundations. For each case, one population control will be selected from Department of Motor Vehicle (DMV) and Medicare databases and, in addition, one unaffected sibling control and - when possible - affected siblings to avoid potential biases and inefficiencies inherent in the use of each type of control. For each study subject, an environmental and occupational pesticide exposure estimate will be derived using California pesticide-use reporting (PUR) data and information about pesticide application on crops in combination with crop patterns shown in satellite images and aerial photographs; in addition, extensive exposure interviews will be conducted with all study subjects. In a three-tiered approach to examine the effects of gene-environment interactions we will: 1) test for association (and linkage) of PD to selected loci associated with PD in earlier studies using multiallelic repeat markers and genotyping; 2) test for association using intragenic single nucleotide polymorphisms (SNPs) of 50 candidate genes arrayed to create """"""""the PD array""""""""; and 3) use future technical possibilities to screen for genome wide associations using array technology to scan 5,000-10,000 SNPs throughout the genome. Data analysis will employ hierarchical modeling procedures to take into account multiple comparison issues and to incorporate prior knowledge such as increased neurotoxicity due to the interaction of gene products and chemicals.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-LKB-C (D1))
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Lawler, Cindy P
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University of California Los Angeles
Public Health & Prev Medicine
Schools of Public Health
Los Angeles
United States
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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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