CYP1A2

CYP1A2 encodes a liver cytochrome P450 enzyme that oxidizes a broad range of xenobiotics and drugs, including caffeine, which it converts to paraxanthine as the rate-limiting step in caffeine clearance. Its activity is strongly inducible — tobacco smoke and heavy coffee intake raise it, and oral contraceptives lower it — and these environmental effects are larger and better established than the effect of any single common variant in the gene. The genome-wide association signal for measured plasma caffeine and caffeine metabolite ratios sits in the bidirectional CYP1A1/CYP1A2 promoter at rs2472297 rather than in the long-studied promoter variant rs762551.