Editors' ChoiceHuman Genomics

Coffee Perks Up Parkinson’s Disease Prevention

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Science Translational Medicine  07 Sep 2011:
Vol. 3, Issue 99, pp. 99ec145
DOI: 10.1126/scitranslmed.3003139

A combination of genetic susceptibility and environmental exposure drives the risk of developing Parkinson’s disease (PD), a neurodegenerative disorder characterized by motor abnormalities. In a genome-wide association study (GWAS) with a twist, Hamza et al. set out to discover genetic drivers of PD in light of a strong nongenetic protective factor: drinking caffeinated coffee. Analyzing 1458 persons with PD and 931 without, they stratified these patients as heavy and light coffee drinkers, then looked for variants associated with PD. They discovered that variants in the GRIN2A gene, which encodes an N-methyl-D-aspartate (NMDA) glutamate receptor subunit involved in neurotransmission in the brain, modified the risk of developing PD among heavy but not light coffee drinkers.

GWASs are usually undertaken to identify common genetic variants, or polymorphisms, that affect the risk of developing a particular disease in a large group of individuals who have widely different environmental exposures. The underlying assumption is that although environment and genetics both contribute to disease, their effects are independent of each other. Of course, this assumption is made for practical reasons: It has been difficult and expensive to collect accurate environmental and genetic exposure data on the large number of individuals needed for a GWAS, and computation time rapidly becomes too lengthy for statistical tests that add environmental variables to models of the hundreds of thousands of identified polymorphisms. A more realistic assumption is that genetic impact on disease is modified by environmental factors such as diet, smoking, exposure to toxins, and drug intake. Likewise, it is the hypothesis that the effects of a drug might depend on one’s genetic makeup that drives pharmacogenetic studies and the promise of personalized medicine.

The Hamza et al. study marks a leap in PD research by demonstrating that genetics and environment together influence disease risk. Their genome-wide association and interaction study in PD patients and healthy individuals accounted for the effects of caffeinated coffee intake and allowed the effects of genotype to vary according to coffee intake. It was this clever combination analysis that enabled the investigators to pinpoint GRIN2A as a new susceptibility gene for PD. Compared with light coffee drinkers with the GRIN2A CC genotype, those with the TC genotype had no statistically significant lower risk of PD. However, among heavy coffee drinkers, those with the TC genotype had a remarkable 59% lower risk of PD than those with the CC genotype. It is intriguing to speculate how caffeine, an adenosine-A2A receptor antagonist, could modify the activity of the NMDA glutamate receptor subunit and so alter neurotransmission in the brain. Incorporating knowledge of the GRIN2A genotype of PD patients in clinical trials for new drugs to treat PD, such as glutamate receptor antagonists and adenosine-A2A receptor antagonists, may make it easier to identify efficacious drugs and moves us one step closer to the goal of personalized medicine.

T. H. Hamza et al., Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson’s disease modifier gene via interaction with coffee. PLoS Genet. 7, e1002237 (2011). [Full Text]

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