Influence of single nucleotide polymorphisms in COMT, MAO-A and BDNF genes on dyskinesias and levodopa use in Parkinson’s disease

Abstract

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias suggests endogenous factors play a significant role in determining their overall prevalence. We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of dyskinesia. Methods: We examined the influence of SNPs in the catechol O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on time to onset and prevalence of dyskinesias in a cohort of 285 pathologically confirmed Parkinson’s disease patients. Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 years vs. 66.4 years, p<0.0001), a longer disease duration (17.0 years vs. 12.0 years, p<0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 mg/day vs. 617.1 mg/day, p<0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for age at disease onset, disease duration, and maximum daily LED. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835mg ± 445mg vs. 508mg ± 316mg; p=0.0056, mean LED: 601mg ± 335mg vs. 398mg ± 260mg; p=0.025). Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual’s lifetime levodopa exposure warrants further investigation.