title: Genetic variation in CYP3A43 is associated with response to antipsychotic medication.
abstract: Genetic variation in cytochrome enzymes is known to affect drug metabolism and influence treatment response. Recently, the rs472660 variant in CYP3A43 has been associated with olanzapine response and clearance. In this study, we investigated the impact of rs472660 and the putatively functional marker rs680055 on antipsychotic response. We genotyped the rs472660 and rs680055 single nucleotide polymorphisms (SNPs) in N = 152 schizophrenia patients of European descent collected at two sample sites who were predominately treated with second generation antipsychotics for up to 6 months. Treatment response was assessed prospectively using Brief Psychiatric Rating Scale (BPRS) scores. Statistical analysis was performed using Chi square and analysis of covariance. The rs680055 SNP was significantly associated with treatment response. Carriers of the minor allele had significantly lower BPRS scores at study end (p = 5.9 × 10(-4)) with 8 % of the variance being explained by rs680055 genotype. Post hoc analyses revealed that this effect was present in both samples and in both genders. The rs472660 SNP was also associated with response (p = 0.027); however, this finding was not significant after multiple test correction. This is the first evidence that the rs680055 missense mutation influences antipsychotic response. Although our finding for rs472660 was only a non-significant trend after correction, our results still support the notion that this SNP may play a role in antipsychotic response. Despite the fact that the functional role of CYP3A43 in antipsychotic metabolism is not fully understood yet, our study provides an important contribution to understanding genetic factors of antipsychotic response.
authors.affiliation: Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto, ON, M5T1R8, Canada, eva.brandl@camh.ca.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Brandl
authors.forename: Nabilah I
authors.initials: NI
authors.lastname: Chowdhury
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Tristram A P
authors.initials: TA
authors.lastname: Lett
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales
chemical_list: D014150:Antipsychotic Agents; D001189:Aryl Hydrocarbon Hydroxylases; C422408:CYP3A43 protein, human