Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson’s disease

Abstract

catechol-o-methyltransferase (coMt) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to parkinson's disease (pD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in chinese pD patients. eleven single nucleotide polymorphisms (Snps) in the coMt gene were genotyped, and clinical data were collected. patients with the tt genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and ct genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with tt and tc (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation. Parkinson's disease (PD) is a common progressive age-related neurodegenerative disease with a prevalence from 41/100,000 in people in their 40 s to more than 1900/100,000 in people in their 80s 1. The main chemical marker of PD is the loss of dopamine production because of the progressive loss of dopaminergic neurons in the substantia nigra in the midbrain 2. The dopamine precursor levodopa (L-dopa) remains the mainstay of treatment and has been the most effective symptomatic therapy in PD since its introduction 3,4. In fact, there are considerable inter-individual and intra-individual variations in the response to L-dopa, including motor fluctuations and dyskinesia 3. "Wearing-off " is a predictable recurrence of symptoms ahead of scheduled doses of dopamine medication, and the symptoms improve after the next dose. Dyskinesia is a kind of involuntary movement from mild to severe and potentially affects 30-40% of PD patients treated with L-dopa. The prevalence of "wearing-off " and dyskinesia was 41-55% over 5 years of treatment with L-dopa. It has been reported that pulsatile stimulation of dopamine receptors accounts for the complications involved in L-dopa therapy. Nutt JG 5 reported that 60-90% of the variability in the pharmacokinetics and pharmacodynamics of antiparkinsonian medicine comes from pharmacogenomics. Understanding the pharmacogenetic factors involved in the mechanism, metabolism, transmission and receptors might lead physicians to optimize L-dopa doses and control motor complications 6. Catech...

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