We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort.
Similar effects of caffeine were observed in men with Parkinson's disease (PD); however, the effect of caffeine in female PD patients is controversial due to caffeine's competition with estrogen for the estrogen-metabolizing enzyme, CYP1A2.
Evidence supporting the effect of substrates, inhibitor or inducers for drug specific metabolizing enzymes in anti-Parkinson's disease drug response includes CYP1A2 in the response to ropinirole and rasagiline, and CYP3A4 in the response to bromocriptine, lisuride, pergolide and cabergoline.
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).
The observed increased risk of PD among female but not male carriers of the rs762551 polymorphism of CYP1A2 and the interactions of caffeine with ESR1 rs3798577 and ESR2 rs1255998 may provide clues to explain the relationship between gender, caffeine intake, estrogen status and risk of PD and need to be replicated.
These findings indicate that CYP2D6, CYP1A2 and, to a lesser extent CYP3A4, may have a role in protecting against Parkinson's disease induced by MPTP and other potential environmental neurotoxins.