Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease

Division of Epidemiology, Department of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA 94305-5405, USA.
European Journal of Neurology (Impact Factor: 4.06). 05/2011; 18(5):756-65. DOI: 10.1111/j.1468-1331.2011.03353.x
Source: PubMed


In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association.
Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression.
Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04).
In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

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Available from: Stephen K. Van Den Eeden, Mar 26, 2014
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    • "In fact, caffeine consumption has been associated with lower risk of PD in several case-control and cohort studies [127–132]. Interestingly, the association between coffee consumption and PD is strongest among subjects that slowly metabolize caffeine and are homozygous carriers of the CYP1A2 polymorphisms, the gene encoding for cytochrome P450 1A2 [133] which is the main enzyme involved in the metabolism of caffeine. "
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    • "The haplotype GTACAT is close to the clinically defined haplotypes CYP1A2*1 M and *1Q [23]. It can be distinguished from other haplotypes because it carries derived mutations at rs762551 (-163C > A*), rs2472304 (2159G > A*), and rs2470890 (5347C > T*), of which rs2472304 and rs2470890 are associated with rapid metabolism of caffeine and anti-depression drugs such as paroxetine [24,25]. Interestingly, these two SNPs are also in the list of highly differential mutations (Table 1), suggesting that they could be potential causal mutations in the CYP1A2 gene for local adaptation of Europeans, leading to specific genotypes and haplotypes in CEU. "
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