Pharmacogenetic profile and the development of the dyskinesia induced by levodopa-therapy in Parkinson's disease patients: a population-based cohort study.

Levodopa-induced dyskinesia (LID) is an adverse effect that negatively impacts the quality of life of patients with Parkinson's disease (PD). Studies report that genetic variations in the genes of the pharmacogenetic pathway of the levodopa (L-DOPA) might be associated with LID development. The goal of the present study was to investigate a possible influence of functional genetic variants in the DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) genes with LID development. A total of 220 patients with idiopathic PD were enrolled. The genotyping for DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) polymorphisms were performed using Restriction Fragment Length Polymorphism (PCR-RFLP). Univariate and multivariate analyses were performed to assess the association of these polymorphisms and risk factors with LID development. Multivariate Cox regression analysis showed increased risk to LID development for both Levodopa Dose Equivalency (LED) (Hazard ratios (HR) = 1.001; 95% CI 1.00-1.01; p = 0.009) and individuals carrying the COMT L/L genotype (HR = 2.974; 95% CI 1.12-7.83; p = 0.010). Furthermore, when performed a Cox regression analysis adjusted for a total LED, we observed that the genotype COMT L/L had a 3.84-fold increased risk for LID development (HR = 3.841; 95% CI 1.29-11.37; p = 0.012). Our results suggest that before treating LID in PD patients, it is important to take into consideration genetic variant in the COMT gene, since COMT LL genotype may increase the risk for LID development.

Influence of DRD1 and DRD3 Polymorphisms in the Occurrence of Motor Effects in Patients with Sporadic Parkinson's Disease.

Parkinson's disease (PD) is a multisystem disorder that affects 2-3% of the population ≥ 65 years of age. The main pharmacologic agent use in the treatment of clinical symptoms of PD is levodopa (L-DOPA). However, the chronic use of L-DOPA might result in the emergence of motor complications such as motor fluctuation and dyskinesia. Previous studies have shown that the inter-individual variability and pharmacogenetic profile of PD patients seem to influence the occurrence of motor complications. For these reasons, the purpose of this study was to evaluate a possible relationship between DRD1 A48G and DRD3 Ser9Gly genetic variants with the occurrence of motor complications in PD patients in a Brazilian population. A total of 228 patients with idiopathic PD were enrolled. Patients were genotyped for DRD1 A48G and DRD3 Ser9Gly polymorphisms using PCR-RFLP. The univariate and multivariate analyses were performed to assess the association of these polymorphisms with the occurrence of motor fluctuation and dyskinesia in PD patients. Multiple Poisson regression analyses showed a protector effect to the occurrence of dyskinesia for individuals carrying of the DRD1 G/G genotype (PR 0.294; CI 0.09-0.87; p ≤ 0.020) after the threshold Bonferroni's. Besides, we verified risk increased to the occurrence of motor complications with daily L-DOPA dosage, disease duration, and users of rasagiline, selegiline, or entacapone (p < 0.05 for all). Our results suggest that the DRD1 A48G polymorphism and the presence of extrinsic and intrinsic factors may role an effect in the occurrence of dyskinesia in PD patients.

The influence of SLC6A3 and DRD2 polymorphisms on levodopa-therapy in patients with sporadic Parkinson's disease.

OBJECTIVES: The aim of this study was to evaluate a possible relationship between DRD2/ANKK1 (rs1800497) and SLC6A3/DAT1 (rs28363170) gene polymorphisms with the response to levodopa (L-DOPA)-therapy in patients with Parkinson's disease (PD). METHODS: One hundred and ninety-five patients with idiopathic PD were investigated. Patients were genotyped for rs1800497 and rs28363170 polymorphisms using PCR-RFLP. Logistic regression was performed to assess the association of polymorphisms with the occurrence of the chronic complications of L-DOPA therapy. KEY FINDINGS: Our results showed association between the occurrence of dyskinesia with an increased greater disease severity (P = 0.007), higher L-DOPA dose (P = 0.007) and use of dopamine agonist (P = 0.020). Moreover, there were significant protective effects for age (P = 0.004) and male subjects (P = 0.006). CONCLUSIONS: Clinical and demographic characteristics of Brazilian PD patients and differences in DRD2 and DAT1 genes may to determine individual variations in the therapeutic response to L-DOPA in the Brazilian PD patients.

MAO-B and COMT Genetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease.

The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P = .02), longer duration of disease (P = .02), longer levodopa therapy duration (P = .01), younger onset of PD (P = .01), and use of COMT inhibitor (P = .02). We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition, we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P = .04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.