Abstract
Background: Impaired dopamine metabolism is associated with Parkinson’s disease (PD). Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients.Methods: A total of 1506 PD patients, 496 MSA patients, and 894 healthy controls were included in this study. Five variants (rs6356 in TH, rs921451 in DDC, rs4680 in COMT, rs1799836 in MAOB, and rs1611115 in DBH) were genotyped in all cases using Sequenom iPLEX Assay technology.Results: After adjusting for gender and age at onset, except for DDC rs921451, which was associated with an increased risk of MSA (p = 0.001, OR = 1.21), no significant differences were found in genotype distribution or minor allele frequencies for the other four variants between PD and MSA patients and healthy controls. In the subgroup analysis, DDC rs921451 was associated with an increased risk for late-onset PD as well as for PD onset in males (p = 0.002 [OR = 1.13] p = 0.003 [OR = 1.15], respectively). In addition, patients harboring the risk allele DDC rs921451 required lower levodopa equivalent daily doses of dopaminergic medication than those without the risk allele (52.00 ± 21.31 mg/day, p = 0.015).Conclusion: None of the five candidate functional variants is a major determinant of the risk for PD or MSA. The modified PD phenotypes associated with these variants requires further confirmation.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by both motor and non-motor symptoms
Dopamine anabolism involves two ratelimiting enzymes, tyrosine hydroxylase encoded by the TH gene and aromatic L-amino acid decarboxylase encoded by the DDC gene, and dopamine catabolism is associated with the activities of catechol-O-methyltransferase, monoamine oxidase B, and dopamine beta-hydroxylase
We found that five functional variants of dopamine metabolism-related genes did not affect the risk of developing PD; the minor allele “C” of DDC rs921451 increased the susceptibility to multiple system atrophy (MSA), especially in males
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by both motor and non-motor symptoms. The exact pathogenesis of neurodegeneration is largely unknown, the impaired activity of dopamine metabolism-related enzymes is known to be associated with PD physiopathology and phenotypes (Devos et al, 2014; Redensek et al, 2019). Neurotransmitter metabolism involves both anabolic and catabolic processes. Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients
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