A genome-wide association study of CYP1A2 activity using tizanidine and caffeine as probe drugs

Cytochrome P450 (CYP) enzymes are the major drug metabolizing enzyme group. The highest level of CYPs is expressed in the liver, and the human cytochrome P450 (CYP) 1A2 is one of the major CYPs playing an important role in the metabolism of clinically used drugs. Muscle relaxant tizanidine and caffeine are sensitive substrates of CYP1A2. CYP1A2 enzyme activity is known to have interindividual variability. In this thesis a genome-wide association (GWA) study of the association of tizanidine and caffeine on CYP1A2 enzyme activity is performed. The pharmacokinetic data of this pooled analysis is based on 8 previously published studies assessing the co-effects and interactions of tizanidine with some other variable on CYP1A2 enzyme activity. Separate GWA studies were performed for men and women. Cigarette smoking was set as a covariate for men and the use of oral contraceptives was set as a covariate for women. These two GWA studies were combined into a genome-wide association meta-analysis and those results are analyzed in this thesis. Furthermore, replication of genome-wide significant findings in previous GWA studies on caffeine was sought. The variants tested in the genome-wide meta-analysis did not reach genome-wide significance (P < 5x10e-8). The replication study of the candidate SNVs in CYP1A2 and AHR loci showed clear signal, although they did not reach the genome-wide significance. This corroborates the previously published findings that CYP1A2 and AHR are the main genes involved in CYP1A2 enzyme activity. However, the results of the meta-analysis support the fact that the changes in CYP1A2 enzyme activity are a combination of various factors and can not be explained fully by genetics