Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Abstract

Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMT val158met , using Val-Val homozygotes as reference category, a protective effect for Val-Met heterozygotes (OR = 0.63, 95% CI: 0.46-0.86, P = 0.004) and Met carriers (OR = 0.66, 95% CI: 0.49-0.88, P = 0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR = 1.30, 95% CI: 1.03-1.65, P = 0.026), and A2-A2 homozygotes using A1-A1 as reference category (OR = 1.80, 95% CI: 1.03-3.15, P = 0.037); (3) in MnSOD Ala9Val, using Ala-Ala homozygotes as reference category, a protective effect for Ala-Val (OR = 0.37, 95% CI: 0.17-0.79, P = 0.009) and for Val carriers (OR = 0.49, 95% CI: 0.24-1.00, P = 0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge.

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

“…BDNF is a neuronal growth and survival peptide that modulates a variety of processes including regulation of the dopamine D3 receptor (DRD3) and could thus be involved in TD through this mechanism (75). The heparan sulfate proteoglycan 2 (HSPG2) gene emerged as the top hit in a GWAS of TD screening by Syu et al (115) and was later replicated in a prospective sample by Greenbaum et al (116) but not in a study by Bakker et al (113).…”

“…Meta-analyses have found three other genes implicated in TD: manganese superoxide dismutase (MnSOD), cytochrome P450 1A2 (CYP1A2), and serotonin 2A receptor (HTR2A) (113). It has also been proposed that BDNF levels contribute to TD and that certain polymorphisms of BDNF may increase response to treatment for TD using ginkgo biloba, a potent antioxidant with neuroprotective effects mediated through enhancing BDNF levels (114).…”

Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms

“…Проводились исследования по поиску ассо-циации между полиморфизмом CYP1A2*1F и поздней дискинезией, выводы которых неоднозначны. Выявлено [47,51] , что длительная антипсихотическая терапия, про-водимая у пациентов с генотипом CYP1A2*1F C/C, чаще приводит к экстрапирамидным побочным эффектам, чем у пациентов, являющихся носителями аллеля А. Однако не-которые исследователи [52,53] не нашли значительной свя-зи между полиморфизмом *1F (-163C>A) и развитием экс-трапирамидных расстройств при приеме антипсихотиков.…”

“…Полиморфизмы гена DRD2 были исследованы наиболее интенсивно, среди них −141C Ins/Del (rs1799732), Taq1A (rs1800497), A-241G (rs1799978), Ser311Cys (rs1801028) и Taq1B (rs1079597) [65]. Проведенные метаанализы продемонстрировали взаимосвязь между полиморфизмом Taq1A гена DRD2 и развитием поздней дискинезии на фоне терапии антипси-хотиками [53,66]. В метаанализе, проведенном С. Zai и соавт.…”

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

“…These include variants within COMT, DRD2, MnSOD, DRD3, HTR2A, CYP1A2 and CYP2D6. [21][22][23][24][25][26] Recently, two genomewide association studies (GWASs) and a large candidate gene study of TD were published, based on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, using two different definitions for TD phenotype. [27][28][29] Although none of the top results reached genome-wide significance, the association of single-nucleotide polymorphism (SNP) rs3943552 in the GLI2 gene with TD was observed in the CATIE sample and independently supported in Jewish Israeli schizophrenia patients of Ashkenazi origin.…”