Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant

• Published in: The pharmacogenomics journal Vol. 10; no. 3; pp. 200 - 218
• Main Authors: Hwang, R, Zai, C, Tiwari, A, Müller, D J, Arranz, M J, Morris, A G, McKenna, P J, Munro, J, Potkin, S G, Lieberman, J A, Meltzer, H Y, Kennedy, J L
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2010
• Subjects: Adult; African Americans; Alleles; Amino Acid Substitution; Antipsychotic Agents - therapeutic use; Antipsychotics; Clozapine; Clozapine - therapeutic use; Complications and side effects; Dopamine D2 receptors; Dopamine D3 receptors; Dopamine receptors; Dosage and administration; European Continental Ancestry Group; Female; Gene polymorphism; Genetic aspects; Genetic diversity; Genetic polymorphisms; Haplotypes; Humans; Linkage Disequilibrium; Male; Meta-analysis; Pharmacogenetics; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Receptors, Dopamine D3 - genetics; Schizophrenia - drug therapy; Single-nucleotide polymorphism; Canada
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2009.65

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.