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Association Study of 27 Annotated Genes for Clozapine Pharmacogenetics: Validation of Preexisting Studies and Identification of a New Candidate Gene, ABCB1, for Treatment Response

Lee, Seung-Tae MD, PhD*†; Ryu, Seunghyong MD; Kim, Suk-Ran MD*; Kim, Min-Ji MS§; Kim, Seonwoo PhD§; Kim, Jong-Won MD, PhD*†; Lee, Soo-Youn MD, PhD*; Hong, Kyung Sue MD, PhD‡∥

Journal of Clinical Psychopharmacology: August 2012 - Volume 32 - Issue 4 - p 441–448
doi: 10.1097/JCP.0b013e31825ac35c
Original Contributions

Objective: Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study.

Methods: Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses.

Results: Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response.

Conclusions: We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy.

From the *Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine; †Center for Genome Research, Samsung Biomedical Research Institute, Samsung Medical Center; ‡Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine; §Department of Biostatistics, Samsung Biomedical Research Institute, Samsung Medical Center; and ∥Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.

Received January 24, 2011; accepted after revision December 16, 2011.

Reprints: Soo-Youn Lee, MD, PhD, Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea (e-mail: suddenbz@skku.edu); Kyung Sue Hong, MD, PhD, Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea (e-mail: hongks@skku.edu).

This study was supported by a grant from the Samsung Genomic Center Research Fund, Samsung Biomedical Research Institute, Samsung Medical Center, Republic of Korea (D-B0-002-1); by a grant from the Korea Health 21 R&D project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A030001); and by a grant from the Korean Ministry of Education, Science and Technology, FPR08A2-130 of the 21C Frontier Functional Proteomics Program.

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© 2012 Lippincott Williams & Wilkins, Inc.