Published: Feb 4, 2014
By John Gever, Deputy Managing Editor, MedPage Today
Many chronic diseases, especially in neuropsychiatry, are believed to result from combinations of genetic risk factors and environmental triggers, but only in a very few have both partners in this dance been identified.
Now, a group of California researchers says they’ve found evidence that pesticide exposure interacts with certain gene variants to promote Parkinson’s disease.
Their study comes on the heels of two others that fingered environmental factors as potentially causative in multiple sclerosis and Alzheimer’s disease, respectively. Together, they suggest that research into triggers for chronic neurodegenerative conditions may be gaining steam.
In the Parkinson’s study, published Monday in Neurology, researchers led by Jeff M. Bronstein, MD, PhD, at the University of California Los Angeles, found that certain variants in the ALDH2 gene for neuronal aldehyde dehydrogenase (ALDH) were associated with increased disease risk in individuals with significant exposures to agricultural insecticides.
That pesticide exposure causes Parkinson’s disease is still not definitively proven, but it is widely assumed to be true on the basis of numerous epidemiological studies, summarized in a meta-analysis published last year.
In the new study, Bronstein and colleagues performed a two-step analysis. First, they ran a bench experiment with 26 pesticides to determine which ones inhibited the neuronal ALDH enzyme, finding 11 that did.
Then, using data from the case-control Parkinson’s Environment and Genes Study, they examined the relationship between Parkinson’s disease and previous exposure to these versus the non-ALDH-inhibiting pesticides, and whether these relationships were affected by participants’ ALDH2 genotypes. The researchers excluded three of the ALDH-inhibiting pesticides because very few study participants had been exposed to them.
Because only a minority of pesticide-exposed individuals develop Parkinson’s disease, some other predisposition is clearly at play. Although it may or may not be genetic, Bronstein and colleagues suspected that ALDH2 polymorphisms may be involved because defects in the enzyme could, when confronted with certain chemicals, produce neurotoxic aldehyde metabolites.
In fact, one of two major ALDH2 haplotypes appeared to drive the association between pesticide exposure and Parkinson’s disease.
In the overall study sample, which included 360 Parkinson’s disease patients and 953 healthy controls, exposure to seven of the eight ALDH-inhibiting pesticides both at home and at the workplace increased the likelihood of a Parkinson’s disease diagnosis with odds ratios ranging from 1.89 to 5.91 (all P<0.05), relative to participants not exposed to ALDH-inhibiting pesticides.
Bronstein and colleagues then conducted separate analyses for participants homozygous for what they called the “clade 1” ALDH2 genotype versus those with one or two copies of the “clade 2” genotype, which were roughly equal in number. They found that pesticide exposure was only weakly associated with Parkinson’s disease in the first group, whereas the association remained pronounced in those with the clade 2 genotype.
The researchers said the results suggested not only a model for how pesticides may induce Parkinson’s disease in genetically susceptible individuals, but also points of possible intervention beyond elimination of pesticide exposures.
Strategies could include boosting normal ALDH function, removing toxic aldehydes from individuals in whom they build up, and/or targeting downstream pathologies caused by the toxic aldehydes.
Obviously, this model still needs confirmation in future studies. But it’s potentially groundbreaking in that, for very nearly the first time, it suggests how a common, chronic disease may emerge from the interaction between a specific environmental trigger and a specific genetic factor.
Striking a Nerve is a blog by John Gever for readers interested in neurology and psychiatry.