Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response.
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.
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Seung-Tae
ST
Lee
Seunghyong
S
Ryu
Suk-Ran
SR
Kim
Min-Ji
MJ
Kim
Seonwoo
S
Kim
Jong-Won
JW
Kim
Soo-Youn
SY
Lee
Kyung Sue
KS
Hong
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D003024:Clozapine