Haplotype analysis of endothelial nitric oxide synthase (NOS3) genetic variants and tardive dyskinesia in patients with schizophrenia

Objectives: Several studies have indicated the involvement of nitric oxide (NO) in the pathogenesis of tardive dyskinesia (TD), an incapacitating adverse movement disorder associated with long-term antipsychotic treatment. In human brain, the NO could be generated by endothelial nitric oxide synthase (NOS3). In this study, we studied whether the genetic variants in human NOS3 gene is associated with TD in patients with schizophrenia. Methods: Two hundred and eighty-two chronic inpatients with schizophrenia treated with typical antipsychotics were recruited in this study. The patients were further grouped by the presence of TD or not according to the Research and Diagnostic Criteria for TD. The genetic variants in the NOS3 gene investigated in this study were -786T > C in the promotor region, 27-bp variable number of tandem repeats (27-bp VNTR) in intron 4, and Glu298Asp in exon 7. The frequencies of genotypes, alleles and haplotypes of the three markers were compared between the TD (n = 153) and non-TD (n = 129) groups. Results: There were no significant associations between the genotypes and alleles of the three markers and TD. However, in the haplotype-based case-control analysis, the frequency of haplotype T-4b-Glu was significantly higher in non-TD than in TD group (TD vs. non-TD = 72.7% vs. 81.0%, permutation P value = 0.021, OR = 0,648, 95% CI = 0.432-0.973). Conclusions: We found that the haplotype T-4b-Glu represents a protective haplotype against TD after long-term antipsychotic treatment. This finding suggests that human NOS3 gene may be involved in the pathogenesis of TD.