Detection of quantitative trait loci affecting caffeine metabolism by interval mapping in a genome-wide scan of C3H/HEJ x APN F-2 mice

Caffeine metabolite ratios have been widely used to measure cytochrome P-45 0 1A2 activity in humans. Serum paraxanthine/caffeine ratio is one such ind ex of this activity. We had previously demonstrated genetic variation of th is trait among inbred mouse strains. In the present study, we have undertak en a genome-wide scan for quantitative trait loci affecting this trait with an interval mapping approach on an F-2 intercross population of acetaminop hen nonsusceptible and C3H/HeJ inbred mice. A statistically significant ass ociation (log-likelihood ratio = 25.0) between a locus on chromosome 9, whi ch colocalized with the murine Cyp1a2 locus, and the plasma paraxanthine/ca ffeine ratio was identified. This result suggested the presence of an expre ssion polymorphism affecting this gene. A second locus was identified on ch romosome 1 (log-likelihood ratio = 9.7) for which no obvious candidate gene has been identified. The influence of this locus on the paraxanthine/caffe ine index was more significant among males (log-likelihood ratio = 6.3) tha n females (log-likelihood ratio = 3.6). A third locus was identified on chr omosome 4 with a less statistically robust association (log-likelihood rati o = 3.4) to the paraxanthine/caffeine phenotype. Collectively, these three loci accounted for 63.2% of the variation observed in the F-2 population fo r this phenotype. These results demonstrate the potential for genetic varia tion arising from factors other than CYP1A2 activity to influence the plasm a paraxanthine/caffeine ratio in mice. This study demonstrates the utility of quantitative genetics in the analysis of polygenic drug metabolism.