Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: Role of oxidative stress pathway genes

Abstract

Keywordsnorth India; Tardive Dyskinesia; oxidative stress; NOS3; NQO1; Single nucleotide polymorphisms; association Tardive Dyskinesia (TD) is a severe debilitating movement disorder with a potentially irreversible course developing in schizophrenia patients under long term treatment with classical neuroleptics. Its development in a subset of patients (~20-25%), familial nature, and concordance amongst twins indicate a possible genetic basis (for review see Muller et al. 2004). In addition to the classical dopaminergic pathway genes, oxidative stress mediated neurotoxic damage is also an important hypothesis proposed to explain the development of TD. Considerable support to OS hypothesis comes from the observations of increased lipid peroxidation in cerebrospinal fluid in patients with TD and antioxidants such as vitamin E alleviate TD symptoms (Adler et al. 1999; for review see Lohr, 2003). Recently a novel antioxidant AD4 has been reported to reduce haloperidol induced vacuous chewing moments in rats (Sadan et al. 2005).In this study, genes involved in the maintenance of cellular redox balance namely, superoxide dismutase 2 (SOD2; MnSOD; Ala9Val), Uncoupling protein 2 (UCP2; 45bp del/ins), neuronal nitric oxide synthase (nNOS; NOS1; His902His, rs2682826), endothelial NOS (eNOS; NOS3; 27bp ins/del), glutathione S transferase (GST; GSTMI, TI; Presence/Null; GSTPI, Ile105Val) and NADPH: quinone oxidoreductase 1 (NQO1, Pro187Ser) were analysed. Schizophrenia patients with TD (n=96) and without TD (n=239) were recruited for the study. SNPs were genotyped using PCR-RFLP and allelic, genotypic and haplotypic association was tested using χ 2 test. Further, to test whether severity of TD was influenced by genotype, mean AIMS score was compared across the genotypic categories for each of the polymorphism using Kruskal Wallis H test.

Association study between glutathione S‐transferase GST‐M1, GST‐T1, and GST‐P1 polymorphisms and tardive dyskinesia

“…None of the SNPs tested were associated with the development of TD. However, they did find an association between the NOS3 variant and severity of TD (Thelma et al, 2007). Therefore, the relationships between ROS-related genes and TD remain controversial.…”

“…A recently developed novel brain-targeted antioxidant, N-acetyl cysteine amide, has been reported to reduce haloperidol-induced vacuous chewing movements in rats (Sadan et al, 2005). Most recently, Thelma et al (2007) performed a genetic association study of several variants of oxidative stress-related genes (SOD2, UCP2, NOS1, NOS1, NOS3, GST-M1, GST-T1, GST-P1, and NQO1) and the development of TD in Indian patients with schizophrenia. None of the SNPs tested were associated with the development of TD.…”

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

“…On the other hand, GCLM codes for the first rate-limiting enzyme in glutathione synthesis and its decreased expression in SZ patient fibroblasts (Tosic et al, 2006) and in peripheral blood of SZ patients (Che et al, 2009) has been reported. A number of studies have reported that oxidative stress is involved in the pathophysiology of TD (Thelma et al, 2007), providing a testable mechanism underpinning the genetic association. MTHFR , a commonly investigated candidate gene in SZ is essential for the conversion of homocysteine to methionine.…”

Association study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients

“…Genetic studies have identified DRD3, DRD2, MnSOD, CYP2D6, CYP1A2, HTR2A to be reproducibly associated with TD, 39,[55][56][57][58][59] although studies in other genes, such as HTR2C, NQO1 and GABRB2, require further investigation. [60][61][62] As nearly all antipsychotics target more than one receptor, it is more likely that TD is not related to one receptor gene, but instead represents a polygenic condition with each gene contributing a small proportion of the risk to this disorder. Gene-gene interaction studies may help to identify and clarify pathways that contribute to TD.…”