Pam Harrison

November 02, 2011

November 2, 2011 (Montreal, Quebec, Canada) — Researchers have discovered that variations in GRIN2A, the glutamate-receptor gene that regulates brain signals controlling movement and behavior, also modulate the risk of developing Parkinson's disease (PD) in heavy coffee drinkers.

Haydeh Payami, PhD, professor of genetics and neurology, State University of New York, and senior research scientist, New York State Department of Health Wadsworth Center in Albany, New York, and colleagues conducted a multicenter genome-wide association and interaction study in an attempt to identify genes that enhance or diminish the protective effects of caffeinated coffee; the ultimate goal would be to use these genes as biomarkers for pharmacogenetic prevention and treatment of PD.

"We and others have previously identified susceptibility genes for PD," Dr. Payami told Medscape Medical News. "The novelty of what we did in this study is that we introduced an environmental factor into the model and when we put coffee in the model, we were extremely lucky in that we pulled out one of the most important genes in the nervous system called GRIN2A, which encodes for glutamate, and glutamate has been implicated in PD for a long time."

The study was reported here during the 12th International Congress of Human Genetics (ICHG)/61st American Society of Human Genetics (ASHG) Annual Meeting and was published in the August 2011 issue of PLoS Genetics.

Epidemiologic Studies

As Dr. Payami explained, experimental studies have long implicated caffeine as being neuroprotective, and epidemiologic studies have shown that caffeinated coffee is protective: people who drink a lot of it seem to have a lower risk for PD. However, reasoning that not everybody stands to benefit equally from coffee's neuroprotective benefit, "we thought we should go after the genes that interact with coffee," she said. The most significant result was the novel appearance of a block of linked single-nucleotide polymorphisms that map to the GRIN2A gene on chromosome 6, Dr. Payami and colleagues report.

This locus had not before been detected in PD genome-wide association studies (GWASs) because its effect was modest. Considered in the context of its interaction with coffee, however, GRIN2A surpassed all PD-associated genes in significance, including the SNCA gene, which until now had had the strongest association with the disease in GWASs.

Dr. Payami and colleagues stratified the cohort into heavy or light coffee drinkers (light included non-coffee drinkers) and carried out another GWAS in each group.

Results showed that heavy coffee drinkers carrying 1 variant of the GRIN2A gene had an 18% lower risk for PD compared with light coffee drinkers, whereas heavy coffee drinkers with another variant of the same gene had a 59% lower risk compared with light coffee drinkers.

Thus, as the investigators point out, PD risk reduction by heavy coffee use — estimated to be 27% on average — was genotype-specific and varied according to GRIN2A genotype.

"Just drinking a lot of coffee doesn't reduce your risk of PD. It depends on the GRIN2A genotype you are carrying," reaffirmed Dr. Payami. What makes this gene-environment interaction study novel — the first of its kind to show a robust interaction between a gene and an environmental factors through a hypothesis-free genome-wide study — is the implication it may have for the treatment of PD.

Currently, 2 different classes of medications have been tested for possible use in PD: adenosine antagonists, which are caffeine-like, and glutamate antagonists, which are GRIN2A related. Both drug classes were found to be safe but not effective enough to achieve regulatory approval.

"Our study proposes a new hypothesis, which is, not everybody in these clinical trials [is] responding equally to these drugs, and if these drugs are anything like coffee, maybe the GRIN2A genotype would be a marker [for treatment response]," Dr. Payami said.

Dr. Payami reported preliminary results from the study at the World Parkinson Congress in Glasgow, Scotland, in September 2010. However, results reported at this year's ICHG/ASHG meeting not only had been replicated in 3 separate data sets but have achieved genome-wide significance since the preliminary report. Results have also been published.

Dr. Payami has disclosed no relevant financial relationships.

PLoS Genet. 2011;7:e1002237. Full text

12th International Congress of Human Genetics (ICHG)/61st American Society of Human Genetics (ASHG) Annual Meeting. Abstract #287. Presented October 15, 2011.

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