Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population

abstract: ...Background Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. Methods We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Results Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. Conclusions The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.

... receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Results Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. Conclusions The COMT rs4680 and MAOB rs1799836

..., low MAOB activity may play a preventive role in PD development. Although the MAOB rs1799836 polymorphism is a synonymous substitution, this single nucleotide polymorphism (SNP) is associated with varying enzyme activity. In fact, synonymous SNPs can cause inactivation of the native splicing donor site, which results in a premature stop codon or exon skipping, yielding a shorter mRNA [ 8 ]. The shorter mRNA results in a truncated protein that is likely rapidly degraded or functionally inactive [ 9 ]. As the G allele of MAOB rs1799836 polymorphism is associated with lower activity of brain MAOB activity [ 10 ], the G allele may be involved in PD susceptibility (protective). The DRD2 rs1800497 T allele (formerly DRD2 TaqI A1) showed reduced DRD2 density in the postmortem brain [ 11 ], decreased receptor binding in positron emission tomography in vivo [ 12 ] and reduction of dopaminergic activity in the CNS [ 13 ]. However, the impact of DRD2 rs1800497 on D2 receptor density has recently been

... Genotyping Assays (ABI) were used for the following (gene, SNP, assay ID): COMT , rs4680, C_25746809_50; MAOB , rs1799836, C_8878790_10; DRD2 , rs1800497, C_7486676_10; DRD4 , rs1800955, C_7470700_30. Statistical analysis To test for associations between SNPs and PD, we defined the ancestral allele using the National Center for Biotechnology Information SNP database as the major allele. We assessed Hardy-Weinberg equilibrium (HWE) via a goodness-of-fit 2 test (Pearson) to compare the observed and

... women. Although men are in a hemizygous state, the genotypes of MAOB rs1799836 for men were coded as homozygous. All "at-risk" alleles were classified into six categories (0-2 and 3, 4, 5, 6, and 7+). Alternatively, all "at-risk" alleles were classified into four categories (0-3 and 4, 5, 6 +). Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for potential confounders. The potential confounders included age

... COMT rs4680, P HWE = 0.443 for MAOB rs1799836 among women, P HWE = 0.111 for DRD2 rs1800497, P HWE = 0.083 for DRD4 rs1800955). As MAOB is located on the X chromosome, rs1799836 among men (no heterozygotes) and women combined deviated from HWE. There were nonsignificant differences in genotypic frequencies between case and control subjects for all of the polymorphisms (P = 0.106 - 0.460). The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD compared with the GG

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