Novel Insights in Pharmacogenetics of Drug Response in Parkinson‘s Disease

Abstract

receptor DRD2 gene, the dopamine transporter (DAT ) gene and μ1 opioid receptor (OPRM1) gene. Motor fluctuations have been associated with a DRD2 gene polymorphism [6], although other studies could not replicate this finding. Conflicting results have been reported concerning the relationship between the occurrence of drug-induced hallucinations in PD and genetic polymorphisms. While some studies demonstrated significant associations between hallucinations and polymorphisms in the DAT gene, the cholecystokinin (CCK ) gene and the apolipoprotein E (APOE) gene, others failed to replicate these results. Associations were found between sleep attacks without warning signs and a polymorphism in the DRD4 gene, the preprohypocretin (HCRT ) gene, the DRD2 gene and the catechol-O-methyl transferase (COMT ) gene. In addition, similar findings were found in recent studies investigating polymorphisms in genes encoding dopamine D 2 and D 3 receptors [7–9] and COMT [10]. Lin and colleagues investigated the role of angiotensin I-converting enzyme in levodopa response [11]. They demonstrated that patients with a homozygote (ins/ins) genotype of the ACE gene had a 2.5-times higher risk of levodopa-induced psychosis, a disabling complication, particularly in the later stage of the disease. The role of angiotensin I-converting enzyme in the development of levodopa-induced psychosis is relatively unexplored. It is necessary to reproduce this study in independent cohorts. We concluded that, in comparison with other subject areas such as psychiatry [12], relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. The focus of pharmacogenetic studies in patients with PD was mainly on genes coding for drug receptors, drug transporters and synaptic drug-metabolizing enzymes (pharmacodynamics). The pharmacogenetic studies in both PD and psychiatry did not, for the most part, Parkinson’s disease (PD) is characterized by brady kinesia, rigidity and tremor, and is the result of degeneration of dopaminergic neurones in the substantia nigra pars compacta. PD has a prevalence of approximately 0.5–1% in persons of 65–69 years, rising to 1–3% among persons of 80 years and older [1]. Twin studies suggest a limited role for genetic factors in the etiology of PD, perhaps most prominently in early-onset forms [2]. The etiology of the common late-onset forms of PD remains largely to be elucidated. Anti-PD drugs, such as levodopa and the direct-acting dopamine agonists, are effective in reducing the motor symptoms of PD. However, these drugs are also associated with the development of motor complications, such as levodopainduced dyskinesia (LID), response fluctuations and side effects, such as hallucinations and excessive daytime sleepiness. In clinical practice, a large interindividual variability in drug response has been noticed. For example, up to 45% of levodopa users develop LID within 5 years, while others remain free of LID for many years [3]. Up to 25% of users of dopaminergic drugs develop hallucinations, whereas others do not [4].