For release: Monday, September 27, 2010
Writing in Nature Genetics,* researchers have found that a gene involved in the immune response is linked to the risk of developing Parkinson’s disease.
The finding “is a small piece of a big puzzle,” said lead author Haydeh Payami, Ph.D., an investigator at the New York State Department of Health Wadsworth Center in Albany. However, it strengthens a theory that Parkinson’s disease may result partly from harmful immune reactions such as inflammation, infections or autoimmunity – when the immune system attacks the body’s own tissues.
Parkinson’s disease attacks neurons in the substantia nigra, a part of the brain that helps control movement. The most common symptoms of the disease are involuntary shaking, slow movement, stiffened muscle tone, and impaired balance.
There are rare purely genetic forms of Parkinson’s disease, but the disease usually is sporadic, meaning that the cause is unclear. In these sporadic cases, researchers suspect that the disease stems from an interplay of genetics and environmental factors. Among these, caffeine consumption and cigarette smoking are associated with a reduced risk of Parkinson’s disease, while there is some evidence that occupational exposure to pesticides increases the risk of the disease.
More recently, investigators have linked a handful of genes to the risk of sporadic Parkinson’s. The two strongest linked genes, MAPT and SNCA, appear to be active primarily in neurons. MAPT encodes a structural protein inside neurons and SNCA encodes alpha-synuclein, a protein believed to regulate signaling both within and between neurons.
The new study identifies a variant of the HLA-DRA gene as a risk factor for Parkinson’s. HLA genes encode proteins that are displayed on the body's cells to help the immune system distinguish self from non-self.
The study involved nearly 4,000 participants, recruited through clinics affiliated with the NeuroGenetics Research Consortium (NGRC) in Oregon, Washington, New York and Georgia. About half of the participants had Parkinson’s and half did not. Their DNA samples were scanned for nearly 1 million single nucleotide polymorphisms (SNPs), which are tiny, usually harmless variants in the genetic code.
In addition to finding an association between Parkinson’s disease and a variant in HLA-DRA, the study confirmed previously reported associations with SNCA, MAPT and a gene called GAK. The variant in HLA-DRA was most strongly associated with late-onset, sporadic cases and was seen more often in men, who are affected by sporadic Parkinson’s disease more often than women.
The researchers also explored the combined effects of having risk variants in all four of the genes - HLA, SNCA, MAPT and GAK. Since everyone has two copies of each gene, the total possible number of risk variants is eight. The risk of Parkinson's disease was doubled for individuals with four risk variants and five-fold higher for individuals with six or more risk variants.
“Each of the genes associated with sporadic Parkinson’s disease has a very small impact on disease risk by itself, but additively, these genes can have a large impact,” said Dr. Payami.
Considered with other bits of evidence, a connection between HLA-DRA and Parkinson’s should spur more research on immune system’s role in the disease, Dr. Payami said. Some studies have shown that there are signs of inflammation in the brains of patients, and that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of the disease. Perhaps not coincidentally, a relative of HLA-DRA called HLA-DRB is the strongest known genetic risk factor for multiple sclerosis, a neurological disease caused by autoimmune reactions.
Dr. Payami and her colleagues found no interaction between HLA-DRA status and prior NSAID use. For example, there was no evidence that having a risk version of HLA-DRA canceled the beneficial effects of NSAID use, or vice versa. Determining the functional significance of HLA-DRA status in Parkinson’s disease will require further investigation, Dr. Payami said.
Data from this study, as well as other Parkinson’s disease genome-wide association studies, are available from the dbGaP database, sponsored by NIH’s National Center for Biotechnology Information.
The NGRC is led by Dr. Payami and is a project to gather information about genetic and environmental risk factors involved in Parkinson’s disease. The NGRC clinics are directed by Cyrus Zabetian, M.D., at the University of Washington in Seattle, Stewart Factor, D.O., at Emory University in Atlanta, and John Nutt, M.D., at Oregon Health and Sciences University in Portland. The study was funded by the National Institute of Neurological Disorders and Stroke, and an award from The Michael J. Fox Foundation for Parkinson’s Research Edmond J. Safra Global Genetics Consortia initiative .
By Daniel Stimson, Ph.D.
*Hamza et al. “Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.” Nature Genetics, published online August 15, 2010.
Last Modified September 27, 2010