Subscribe to eTOC

New Insights into the Interplay of Gene Variants and Pesticide Exposure in Parkinson’s Disease

NICE, France—Pesticide use has been associated with an increased risk of Parkinson's disease (PD). Now new research presented here at the International Congress of Parkinson's Disease and Movement Disorders offers insight into the role that genetic variants may play in modulating that risk.

The findings suggest that the risk for PD associated with exposure to pesticides may be mediated by the presence of certain genetic variants.

Using an "exposed-only" approach involving only people who were known to use or apply pesticides, researchers found several single nucleotide polymorphisms (SNPs) present at a significantly greater frequency among those with pesticide exposure and PD than among those who were also exposed but did not have PD, said Samuel Goldman, MD, MPH, associate professor of medicine at the University of California, San Francisco (UCSF).

"The interaction between pesticides and genetics is very difficult to test because you need these huge subsets," Dr. Goldman said. "So most large genetic studies don't collect environmental data and so there's been a real deficiency in the ability to look at gene-environment interactions…This is another approach that maximizes the power in an exposed-only analysis."

The approach allows interactions to be seen even with smaller samples of those with exposure to a particular agent and who have the disease.

The case-control study was part of the Agricultural Health Study, which included 52,000 pesticide users and their spouses in Iowa and North Carolina. Researchers performed genotyping on 100 subjects who had been diagnosed with PD and 371 matched controls, analyzing for 123 genes and a total of 3,309 SNPs with the potential for PD involvement—metabolic enzymes, xenobiotic membrane transporters, and antioxidant or glutathione-related genes. They looked at subcohorts for the insecticide rotenone, the herbicide paraquat, the insecticide permethrin, cycloidiene insecticides, and the herbicide 2,4-D.

Researchers reported on four SNPs that were significantly associated with PD. One, among those with rotenone exposure, was for the nucleoredoxin gene (p = 0.04; OR = 6.8), which is important for protection against oxidative stress. Another, among those exposed to 2,4-D—a major component of Agent Orange—was a SNP in the gene coding for cytochrome P450 2E1 (p = 0.03; OR = 14.9), which metabolizes a wide variety of chemicals.

In gene-wide burden tests, they found that SNPs for particular genes were more likely for those with PD than those without. Among those with rotenone exposure, for instance, variants were higher in those with PD for the gene ABCB1, which encodes P glycoprotein, a membrane transporter that prior studies have shown binds rotenone and transports it across the cell membrane, Dr. Goldman said.

This new approach may not have been used to study movement disorders or any neurodegenerative conditions before, Dr. Goldman said, and it provides added evidence that genetics and pesticides seem to play an interwoven role in the development of PD.

"It reinforces the evidence that pesticide exposure and genes are involved in pesticide metabolism," he said. "Hopefully others will take this same approach with an exposed-only analysis."

Caroline Tanner, MD, PhD, FAAN, another author on the study and professor of neurology at UCSF, said the findings point to the heterogeneity of mechanisms that seem to be involved in pesticide-genetic interactions.

Alexis Elbaz, MD, PhD, research professor at the Center for Research in Epidemiology and Population Health (INSERM) in Paris who has also studied pesticides' role in PD, said he thought the findings were impressive and show that "not everyone who is exposed to these pesticides has an increased risk, so the risk associated with pesticides depends on your genetic background."

But he wondered about the usefulness of the findings since there was no genetic testing performed in those who were not exposed to the pesticides.

"We have done these sorts of studies, too, and it's interesting to explore these gene-environment interactions, to understand how it works and to see people who are more susceptible than others," he said. "But the implications of it are not very clear because you're not going to test persons before they use pesticides…How can you apply this information?"

Link Up for Related Information:

International Congress Abstract 1515: Kaye J, Lima L, Tanner C, et al. Exposed-only analysis of gene-pesticide interaction in Parkinson's disease (PD).