Superfund Research Program
Environmental and Genetic Risk Factors for Parkinson's Disease
Project Leader: Harvey Checkoway (University of California-San Diego)
Grant Number: P42ES004696
Funding Period: 1995 - 2009
Final Progress Reports
This investigation is examining the roles of environmental factors and genetic susceptibility traits in the causation of Parkinson’s disease (PD). The environmental agents of greatest interest are those that have the potential to damage (or protect) neurons that produce the neurotransmitter dopamine—depletion of dopamine is the underlying cause of PD. In addition, Dr. Checkoway and his research team are investigating mutant forms of genes that may render persons especially sensitive to the effects of environmental chemicals.
The researchers are continuing to enroll PD cases and controls from the membership of Group Health Cooperative of Puget Sound, Washington. During the preceding year, they have made substantial progress on both the epidemiological and molecular biological aspects of the project. They have continued to enroll cases and controls into the study. Their ultimate target recruitment is 400 cases and 600 controls. Questionnaires eliciting data on environmental exposures, medical history, medication use, smoking, and diet have been administered.
The data from the project’s study demonstrating the now predictable inverse relation between smoking and PD risk have been included in a pooled analysis of over 2000 cases and 3000 controls from multiple epidemiologic studies of PD. Pooled analyses that are underway will characterize the association further and with increased statistical precision. Analyses of exposures to pesticides indicate possible associations with certain exposed occupations, although project investigators have not seen evidence for associations of PD with home use of pesticides. The occupational pesticide association was strongest among applicators. With respect to occupational exposures other than pesticides, the most striking result was an elevated risks for PD associated with employment in health care professions in both men and women, which may be interpreted as consistent with the hypothesis that airborne infectious exposures are related to PD. Employment for 20 yrs or more in jobs classified according to the combined category of lead and copper exposures, based on expert industrial hygiene ratings, was related to increased PD risk. No associations were detected for solvent exposures.
Project investigators also examined associations of PD with co-morbid conditions and with medications that potentially relate to PD pathogenesis mechanisms (inflammation, apoptosis). There was a reduced PD risk among men with a history of diabetes. This effect was most pronounced in non-smoking men. Diabetes history was unrelated to PD in women. No other co-morbid conditions were associated with PD. Use of aspirin or aspirin-containing drugs was associated with a decreased risk, which is consistent with an anti-inflammatory effect. In contrast, persons who used β-blocker medications had a significantly elevated risk of PD.
Project investigators continued to examine the role of genetic polymorphisms as susceptibility markers. Among the numerous genetic variants investigated to date, the most consistent finding has been an increased risk among carriers of the G allele of the monoamine oxidase B (MAO-B) gene, which is involved in dopamine metabolism and activation of pro-neurotoxicants. Sequencing of the promoter region of the dopamine transporter (DAT1) gene led to the identification of 8 haplotypes whose gene products demonstrated functional differences. These haplotypes are being examined further in relation to gene/gene and gene/environment interactions.