The investigators performed an innovative two-step statistical analysis to study Parkinson's disease risk factors. They found that complex interactions between common gene variants contribute to Parkinson's disease risk in women.
The researchers postulate that environmental exposures often are sufficient to lead to Parkinson's disease risk in men.
"For women, genetic predisposition may be more important because they are less exposed to environmental risk factors linked to Parkinson's disease in previous research. Also, estrogen may protect women's brains from the effects of these environmental factors," says Demetrius Maraganore, M.D., Mayo Clinic neurologist and one of the study authors.
The medical community has known for many years that the incidence of Parkinson's disease is lower in women than in men, but the exact reasons have remained a mystery. Now, Dr. Maraganore and colleagues at Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., have proposed an explanation.
"The causes of Parkinson's disease differ between men and women," says Dr. Maraganore. "Traditionally, men have been out in the workforce becoming exposed to environmental risk factors such as pesticides and industrial chemicals or suffering head injuries.
By contrast, women have been less exposed to these factors and require a stronger genetic susceptibility to develop Parkinson's.
Furthermore, estrogen, the main sex hormone in women, reduces the risk of developing the disease.
"For a woman to get Parkinson's disease, she has to inherit certain gene variants," says Dr. Maraganore. Hormonal factors combined with more limited environmental exposure may help protect women from Parkinson's disease.
In this study, Mayo Clinic researchers discovered an interaction between common variants of two genes -- ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and a-synuclein -- that leads to a significantly higher risk of Parkinson's disease than commonly occurs in the population. Rare mutations in these two genes as well as in a gene called "parkin" also have been shown to cause rare inherited forms of Parkinson's disease.
The Mayo Clinic researchers performed genetic tests on blood samples from 319 unrelated Parkinson's disease cases and 196 cases with no evidence of Parkinson's disease. These patients are all part of ongoing Mayo Clinic studies of the causes of Parkinson's disease led by Dr. Maraganore and his colleague, Walter Rocca, M.D., Mayo Clinic epidemiologist.
Following the genetic studies, the researchers conducted a unique statistical analysis. Step one involved an automated search (recursive partitioning) for possible genetic interactions from the data collected about the study participants' DNA. Following this search, the investigators conducted a test of the significance of the gene interactions discovered.
The Mayo Clinic researchers currently are conducting further studies to test their hypothesis that environmental factors play a greater role in Parkinson's in men, while genetic factors play a larger role in women.
Parkinson's disease is a progressive condition that causes a movement disorder including generalized slowness, tremulousness and immobility. It may develop when motor-control circuits deep in the brain become disordered as a result of selective-cell degeneration.
The National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Stroke, and Mayo Foundation funded this study.
Lisa Copeland
507-284-5005 (days)
507-284-2511(evenings)
email: newsbureau@mayo.edu
Journal
Movement Disorders