Superfund Research Program
The Role of Gene/Environment Interactions in the Etiology of Parkinson's Disease
Parkinson's disease (PD)is a chronic neurodegenerative disease that affects approximately one million people in the United States - primarily at ages 50 years and older, striking men more commonly than women. The clinical hallmarks of PD are abnormally slowed movement, muscle rigidity, tremor of muscles at rest, and difficulties walking and standing. The underlying physical basis of PD is a loss of brain cells that produce dopamine - the neurotransmitter required for coordinated muscle movements.
The causal factors are essentially unknown for the vast majority of PD cases - only about 10% of PD cases can be attributed to direct inheritance. Experimental and epidemiologic evidence accumulated over the last 20 years suggests that environmental toxicants, including those commonly found at hazardous waste sites, may play significant roles in PD etiology. Current hypotheses emphasize the importance of gene/environment interactions, whereby persons who carry genotypes predictive of either a diminished capacity for chemical detoxification, or enhanced propensity to activate pro-neurotoxicants, are most susceptible to environmentally-induced PD.
A team of SBRP-funded researchers at the University of Washington, led by Harvey Checkoway, is continuing an epidemiologic investigation begun in 1993 to examine the contributions of environmental factors and genetic susceptibility traits to the causation of PD. This research focuses on potential associations of PD with exposures to pesticides, metals, and industrial solvents, and on factors that may reduce risk, including cigarette smoke and caffeine. Dr. Checkoway is also investigating variant forms of genes that may render persons especially sensitive to the effects of environmental chemicals. An underlying hypothesis of this research is that chemicals that provoke oxidative stress reactions destroy dopaminergic neurons preferentially among persons with genetically determined susceptibilities.
The research team continues to enroll incident PD cases and controls from the Puget Sound, Washington area. PD patients are referred by physicians and diagnoses verified by chart reviews by 3 neurologists. A nurse-practitioner meets with each participant to administer a structured in-person questionnaire, eliciting data on environmental exposures, medical history, medication use, smoking and diet. The nurse also draws blood samples for subsequent DNA extraction and analyses of variant genes.
Study results to date:
- Support previous studies showing an inverse relation between cigarette smoking and PD risk. For decades, cigarette smokers have consistently been found to have lower PD risks than non-smokers, suggesting a possible "neuroprotection" afforded by nicotine or other components of cigarette smoke.
- Contradict several recent studies that suggested potentially protective effects of caffeine. No association was identified between PD and either coffee consumption or total caffeine intake.
- Indicate a reduced PD risk among persons who consume two or more cups of tea per day. This finding was not anticipated, but deserves further investigation as tea contains anti-oxidants chemicals.
- Indicate possible associations with some types of pesticides from occupational sources (e.g., crop farming and pesticide application), but no evidence for associations of PD with home use of pesticides.
Dr. Checkoway's investigation of genetic susceptibility traits has been extensive. To date, his research team has studied genes involved in dopamine metabolism/uptake and xenobiotic activation/detoxification, including: monoamine oxidase B (MAO-B), monoamine oxidase A (MAO-A), catechol-O-methyl transferase (COMT), dopamine D2 receptors, cytochrome P450 (CYP) 2D6, CYP2E1, CYP1A1, glutathione S-transferases (GST, M1, T1, Pi), superoxide dismutase (SOD1, SOD2), microsomal and soluble epoxide hydrolase (mEH, sEH), and paraoxonase (PON1). The researchers are complementing the search for novel mutations with in vitro studies of enzymatic functional significance.
The researchers did not find any significant overall or gender-specific interactions of smoking with polymorphisms of the dopamine D2 receptors or the MAO-A gene. The most notable result thus far has been the identification of an association of PD risk with a form of the MAO-B gene. The enzyme encoded by this gene catabolizes dopamine and activates some neurotoxic chemicals that may be involved in PD induction, making it is especially relevant to PD. Dr. Checkoway's group discovered that individuals with a single nucleotide polymorphism in a non-coding portion of the MAO-B gene (an A ® G substitution in intron 13) have approximately two times the increased risk of PD, and that the seemingly protective effect of cigarette smoking is found only among persons with the G allele substitution. Further analyses revealed that the MAO-B gene/environment interaction is confined to men. Women smokers have a reduced PD risk irrespective of MAO-B gene type. Estrogen is known to have various neuroprotective effects, and there is evidence that estrogen can inhibit MAO-B in the liver, kidney and uterus. The inhibitory effect of estrogen on MAO-B may operate by a different mechanism than tobacco smoke, thus it is possible that estrogen and tobacco smoke constituents interact in different ways with MAO-B to modify PD risk.
This research may ultimately provide valuable new information that can lead to PD prevention strategies, and may serve as a model approach for investigating the complex interplay between low-level environmental exposures and genetic factors on risk for neurodegenerative disorders.
For More Information Contact:
To learn more about this research, please refer to the following sources:
- Checkoway H, Powers KM, Smith-Weller T, Franklin GM, Longstreth WT, Swanson PD. 2002. Parkinson's disease risks associated with cigarette smoking, alcohol use, and caffeine intake. Am J Epidemiol 155:732-738. PMID:11943691
- Kelada SN, Costa-Mallen P, Costa LG, Smith-Weller T, Franklin GM, Swanson PD, Longstreth WT, Checkoway H. 2002. Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease. Neurotoxicology 23(4-5):515-519. PMID:12428723
To receive monthly mailings of the Research Briefs, send your email address to firstname.lastname@example.org.