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Genes, Paraquat and Parkinsonís Disease

Genes combined with exposure to the herbicide paraquat, may contribute to a person’s risk of developing Parkinson’s disease (PD), according to a new study published online in Movement Disorders on October 8, 2012.  In particular, farmers who use paraquat and are missing copies of a gene called GSTT1 are at greater risk of developing PD than others.

Many experts think that Parkinson’s disease is caused by a combination of genetic and environmental factors, which may vary from person to person. Scientists had already observed that farmers who used paraquat, a widely used herbicide, have an increased risk of PD compared with farmers who don’t use it. They also saw that treating rodents with paraquat gives the animals a PD-like disease.

Although most people who use paraquat do not develop PD, researchers led by Samuel Goldman, M.D., M.P.H., at the Parkinson’s Institute and Clinical Center in Sunnyvale, CA, wondered whether two genes called GSTT1 and GSTM1, which help to detoxify chemicals like paraquat, could affect risk for PD in people exposed to it.

People who inherit missing copies of GSTT1 or GSTM1 genes - common in Caucasians - could be more susceptible to paraquat-caused PD, Dr. Goldman reasoned. So he and his colleagues collected blood samples and examined the DNA from a group of people (mostly farmers) who routinely applied pesticides such as paraquat.

These people were part of the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. Of the study participants, 87 had PD and 343 did not have PD (control group). The participants reported whether they had a) never used paraquat, b) used paraquat for four years or less, or c) used paraquat for more than four years.

Results

  • People can have two copies (one inherited from the mother, and one from the father) each of the GSTT1 and GSTM1 genes. In the study group, 223 people (52 percent) were missing both copies of GSTM1, and 95 (22 percent) people had mutations that deleted both copies of GSTT1. Researchers found that 73 (17 percent; all men) people had used paraquat.
  • As shown in previous studies, people who had used paraquat had a higher risk of PD than those who had not been exposed to it, and the PD risk increased with years of paraquat use.
  • People who used paraquat and were missing both copies of their GSTT1 gene had an 11-times greater risk of developing PD than those who used paraquat but had both gene copies. Their risk of PD rose with years of paraquat use.
  • In contrast, losing the GSTM1 gene did not increase the risk of PD for people who used paraquat.

 

What Does It Mean?

Paraquat exposure has been consistently associated with PD. However, even a threefold increased risk for PD means that the vast majority (more than 90 percent) of those exposed to paraquat will not develop PD.

Here, scientists identified genes that, when combined with environmental toxin exposure, can greatly affect the risk of developing PD. This finding may help explain why some people who use paraquat develop PD, while others don’t. People missing both copies of GSTT1 lack any GSTT1 enzyme, which may hinder their cells’ abilities to repair damage caused by paraquat.  If too many dopamine-producing neurons die as a result of this damage, PD can develop. In contrast, GSTM1 mutations were associated with lower risk of PD.

Loss of the GSTT1 and GSTM1 enzymes is common in the general population. Previous studies have shown that about 20 percent of Caucasians and 50 percent of Asians lack any GSTT1 enzyme, and 50 percent of both populations lack GSTM1. Data on the direct association between these genes and PD have been conflicting. These mutations on their own may drastically alter PD susceptibility. However, this study showed that, in combination with paraquat use, GSTT1 mutations can increase PD risk.

Like most studies, this one has limitations. Only 15 people who used paraquat also had mutations in both copies of GSTT1. Therefore, this study should be repeated in a larger group to confirm the results. In addition, the people in the study were probably exposed to many pesticides other than paraquat, which could have affected PD risk. Also, the researchers relied on the study participants to recall their past paraquat use, which may not have always been accurate.

If scientists are able to confirm these results in other groups, the study could have some important implications. For example, doctors could screen people who routinely use pesticides for missing copies of GSTT1, and advise those with missing copies to avoid paraquat use.  Also, future research could explore how the GSTT1 enzyme protects against PD caused by paraquat, and if this enzyme’s properties could perhaps be exploited for therapeutic use.

Reference: Samuel M. Goldman, Freya Kamel, G. Webster Ross, Grace S. Bhudhikanok, Jane A. Hoppin, Monica Korell, Connie Marras, Cheryl Meng, David M. Umbach, Meike Kasten, Anabel R. Chade, Kathleen Comyns, Marie B. Richards, Dale P. Sandler, Aaron Blair, J. William Langston, and Caroline M. Tanner. Genetic Modification of the Association of Paraquat and Parkinson’s Disease. Movement Disorders, 2012, published online October 8. DOI: 10.1002/mds.25216

Source Date: Nov 30 2012