title: Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Epidemiology, Department of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA 94305-5405, USA. rpopat@stanford.edu
authors.forename: R A
authors.initials: RA
authors.lastname: Popat
authors.forename: S K
authors.initials: SK
authors.lastname: Van Den Eeden
authors.forename: C M
authors.initials: CM
authors.lastname: Tanner
authors.forename: F
authors.initials: F
authors.lastname: Kamel
authors.forename: D M
authors.initials: DM
authors.lastname: Umbach
authors.forename: K
authors.initials: K
authors.lastname: Marder
authors.forename: R
authors.initials: R
authors.lastname: Mayeux
authors.forename: B
authors.initials: B
authors.lastname: Ritz
authors.forename: G W
authors.initials: GW
authors.lastname: Ross
authors.forename: H
authors.initials: H
authors.lastname: Petrovitch
authors.forename: B
authors.initials: B
authors.lastname: Topol
authors.forename: V
authors.initials: V
authors.lastname: McGuire
authors.forename: S
authors.initials: S
authors.lastname: Costello
authors.forename: A D
authors.initials: AD
authors.lastname: Manthripragada
authors.forename: A
authors.initials: A
authors.lastname: Southwick
authors.forename: R M
authors.initials: RM
authors.lastname: Myers
authors.forename: L M
authors.initials: LM
authors.lastname: Nelson
mesh_terms: D000368:Aged; D002110:Caffeine / Q000378:metabolism* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000235:genetics*
chemical_list: D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D043705:Receptor, Adenosine A2A; D002110:Caffeine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2