The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease

OBJECTIVES: The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. MATERIALS AND METHODS: A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. RESULTS: No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). CONCLUSION: The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.     

Association of a monoamine oxidase B allele with Parkinson's disease

Monoamine oxidase B(MAO-B) is implicated in the cause of Parkinson's disease(PD) because of its role in metabolizing the neurotoxin 1-methyl–4-phenyl–1,2,3,6-tetrahydropyridine, and forming H₂O₂ during dopamine metabolism. Altered MAO-B activity has been observed in PD platelets. Polymerase chain reaction was used to amplify a portion of the MAO-B gene. Polymerase chain reaction products were screened with restriction enzymes to identify fragments useful for single-stranded conformational polymorphism analysis. A single-stranded conformational polymorphism was identified in an MAO-B polymerase chain reaction product after Hae III digestion. One hundred twenty-one control individuals were allelotyped with frequencies of 0.45 and 0.55 for alleles 1 and 2, respectively. Frequencies of 0.62 and 0.38 (1 and 2, respectively) were observed in a population of 46 patients with PD. The presence of MAO-B allele 1 is associated with a relative risk for PD of 2.03-fold (confidence interval, 1.44–2.61; p < 0.02). For comparison, a monoamine oxidase A polymorphism was used to determine allelic frequencies in these same populations and no statistically significant differences were found. These results suggest that an inherited variant of MAO-B may be involved in a genetic predisposition for PD.     

Platelet monoamine oxidase B and plasma beta-phenylethylamine in Parkinson's disease

OBJECTIVE: To evaluate the correlation between changes in platelet monoamine oxidase type B (MAO-B) activity and plasma beta-phenylethylamine (PEA) concentrations in patients with Parkinson's disease and controls. METHODS: Platelet MAO-B activity and plasma PEA were measured with gas chromatography-mass spectrometry (GC-MS) in patients with Parkinson's disease treated with levodopa (12 men and 12 women) or selegiline (three men and three women), and physically healthy subjects as a control group (10 men and 10 women). RESULTS: Platelet MAO-B activity was significantly higher in the Parkinson's disease group (mean 542 (SD 318) pmol/10(7) platelets/30 min) than in the control group (mean 349 (SD 307) pmol/10(7) platelets/30 min) (p<0.05). By contrast, the plasma PEA concentrations in patients with Parkinson's disease were significantly lower than in the control group (mean 532 (SD 243) pg/ml; 931 (SD 560) pg/ml) (p<0.01). The plasma PEA concentrations in patients with Parkinson's disease treated with selegiline were prominently higher than in patients with no selegiline treatment (p<0.001). There was a significantly negative correlation between platelet MAO-B activity and plasma PEA concentrations in patients (n=24, r=-0.466, p<0.001). CONCLUSIONS: The increase in platelet MAO-B activity and decrease in plasma PEA concentrations in patients with Parkinson's disease may be involved in the pathophysiological processes of the disease, and these changes are reversed by treatment with selegiline.     

Platelet monoamine oxidase B activity in Parkinson's disease: A re-evaluation

Summary An increase in platelet monoamine oxidase (MAO) B activity in drug-free parkinsonians (n=6) compared with healthy controls (n=10) has been confirmed using both phenylethylamine (PEA) and dopamine as substrates, reaching statistical, significance in the case of PEA oxidising activity (p<0.05). Thus, certain reports of raised platelet MAO B activity towards PEA but decreased activity towards dopamine in parkinsonians, raising the possibility of the existence of an abnormal form of MAO B in this condition, cannot be supported.     

Role of gene polymorphism of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), cytochrome P450 2D6 (CYP2D6) and N-acetyltransferase 2 (NAT2) in pathogenesis of Parkinson's disease

Factors underlying pathogenesis of diseases are currently being searched. In recent years increasing number of reports on genetic background of central nervous system diseases have appeared. In the search of factors that can precipitate degeneration of dopaminergic neurons the role of enzymes catabolising xenobiotics (CYP2D6, NAT2) and enzymes metabolising catecholamines (COMT, MAO B) has been postulated. Polymorphism of genes coding for isotypes characterised by different biological activity could be responsible for the propensity for Parkinson's disease, progression and efficacy of pharmacotherapy of the disease.     

Polymorphisms of catechol-0-methyltransferase (COMT), monoamine oxidase B (MAOB), N-acetyltransferase 2 (NAT2) and cytochrome P450 2D6 (CYP2D6) gene in patients with early onset of Parkinson's disease

The aim of the present study was to evaluate the contribution of MAOB, COMT, NAT2 and CYP2D6 gene polymorphisms to early onset Parkinson's disease (PD). The study enrolled 134 patients with Parkinson's disease (early onset-EOPD--67 patients, and late onset--LOPD--patients), and 66 healthy individuals. Polymerane chain reaction restriction fragment length polymorphism (PCR-RFLP) methods were used for genotyping. Univariate analysis revealed a significant two-fold higher EOPD risk among carriers of MAOB allele A or AA genotype. Multivariate analysis revealed that MAOB allele A was an independent factor predisposing to EOPD. It was shown that neither NAT2, CYP2D6 nor COMT genotype was associated with PD.     

Monoamine oxidase B (MAOB)-containing structures in MAOA-deficient transgenic mice

Monoamine oxidase (MAO)-containing structures were studied for the first time in type A MAO (MAOA)-deficient transgenic mice (Tg8) derived from C3H strain, using MAO enzyme histochemistry. In this mutant line, MAOA activity was not detected in neurons of the locus coeruleus. In contrast, in their dorsal raphe neurons, we noted an intense activity of type B MAO (MAOB). Based on pharmacological MAOA suppression experiments employing a specific inhibitor (clorgyline), we confirmed that the localization of MAOB-positive structures are not different between Tg8 mutant and normal C3H line. Many of MAOB-positive structures which have not been described previously in the rat, cat and primates were described in this study. In the forebrain, MAOB-containing neurons were discriminated in the striatum, septal nuclei, major island of Calleja, diagonal band, medial forebrain bundle, ventral pallidum and amygdaloid nucleus. Stained neurons in the thalamus and hypothalamus were much more extensively distributed in the mouse than the rat. Pontine laterodorsal tegmental neurons showed MAOB activity. The present data suggest that serotonin, a preferential substrate for MAOA, can be oxidized by MAOB in MAOA-deficient Tg8 mice.     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

目的 探讨单胺氧化酶B(MAO-B)基因型和等位基因与早发帕金森病(early-onset Parkinson's disease,EOPD)的关系.方法 采取聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,研究65例EOPD患者(<50岁)、60例晚发PD(late-onset Parkinson's disease,LOPD)患者(≥60岁)和66名健康对照者(<50岁)的基因型频率和等位基因频率的分布差异.结果 EOPD组的AA基因型频率(49/65,75.4%)高于健康对照组(34/66,51.5%),差异有统计学意义(x2=8.075,P=0.018);LOPD组分别与EOPD组、健康对照组的从基因型频率比较,差异无统计学意义;男性EOPD组分别与男性健康对照组、男性LOPD组,女性EOPD组分别与女性健康对照组、女性LOPD组的AA基因型频率比较,差异无统计学意义;男性LOPD组与男性健康对照组、女性LOPD组与女性健康对照组的AA基因型频率比较,差异无统计学意义.EOPD组的A等位基因频率(107/130,82.3%)高于健康对照组(87/132,65.9%),差异有统计学意义(X2=9.165,P=0.002);LOPD组分别与EOPD组、健康对照组的A等位基因频率比较,差异无统计学意义;男性EOPD组的A等位基因频率(60/70,85.7%)高于男性健康对照组(51/72,70.8%),差异有统计学意义(x2=4.606,P=0.032);女性EOPD组的A等位基因频率(47/60,78.3%)高于女性健康对照组(36/60,60.0%),差异有统计学意义(x2=4.728,P=0.030);男性LOPD组分别与男性EOPD组、男性健康对照组,女性LOPD组分别与女性EOPD组、女性健康对照组的A等位基因频率比较,差异均无统计学意义.结论 MAO-B的从基因型频率增高是EOPD组发病的危险因素;MAO-B的A等位基因频率增高是EOPD组、男性EOPD组及女性EOPD组发病的危险因素.     

Peripheral blood cell activities of monoamine oxidase B and superoxide dismutase in Parkinson's disease

Summary Monoamine oxidase type B (MAO-B) and superoxide dismutase (SOD) are two enzyme stystems that are potentially relevant to an oxidative stress model of Parkinson's disease (PD) causation. Activities of MAO-B in platelets (nmol/10⁸ cells/hr) and total SOD in lymphocytes (U/mg protein) were assayed among 28 cases of idiopathic PD and 22 controls. As anticipated, MAO-B was lowest in PD cases on selegiline (L-deprenyl) therapy (mean 1.10). There was a slight deficit of MAO-B among male cases not taking selegiline compared to controls (3.78 vs. 4.15), but the opposite trend was observed for females (6.18 vs. 4.16). SOD was slightly higher in cases (7.40), than controls (6.81). Excess SOD among PD cases was seen irrespective of gender, age, or selegiline treatment, although none of the differences was statistically significant Future research on SOD should take advantage of the availability of assays specific for the cytosolic and mitochondrial forms of the enzyme.     

Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy

Recent studies have reported an association between the glucocerebrosidase (GBA) gene and Parkinson's disease (PD). To elucidate the role of this gene in our population, we screened 395 PD patients and 483 controls from southern Italy for the N370S and the L444P mutations. We found 11 patients (2.8%) carrying a heterozygous mutant GBA allele, whereas only one control subject (0.2%) had a heterozygous substitution (P = 0.0018). These results strongly suggest that Italian carriers of a GBA mutation have an increased risk of developing PD. © 2007 Movement Disorder Society     

Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease

We tested for gender-specific interactions between smoking and genetic polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1 or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's disease (PD) cases and 296 age- and gender-matched controls. The odds ratios (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13-0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18-2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001, P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV or DRD2 Taq1B genotypes. These results suggest that a strong gender difference exists with respect to the modifying effect of MAO-B genotype on the smoking association with PD.     

Catechol-O-methyltransferase and monoamine oxidase B genes and susceptibility to sporadic Parkinson's disease in a Polish population

Recent reports have proved that genetic factors play a role in the pathogenesis of sporadic Parkinson's disease (PD). It has been suggested that polymorphisms in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might increase the risk of PD. A total of 210 Polish patients with sporadic PD and 152 healthy controls were studied. The MAOB and COMT polymorphisms were identified using the polymerase chain reaction-restriction fragment length polymorphism method. The MAOB allele and genotype frequencies in PD patients did not differ significantly from the controls. A statistically lower frequency of the COMTLL genotype in patients with parkinsonism was found. The combined haplotype of the MAOB G (G/G) and COMTHL genotype showed a fourfold increase (p < 0.05) in the risk of PD in female patients in this Polish population.     

Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population

Objectives – Previous studies have found associations between Parkinson’s disease (PD) and polymorphisms located within both the alpha‐synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease. Methods – We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3′ gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed. Results – Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263‐bp allele, rs356165 and rs356219). Conclusion – LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3′ regions.     

中国人群单胺氧化酶-B基因多态性与帕金森病相关性研究

目的 探讨人多巴胺代谢酶—单胺氧化酶B(MAO—B)基因内含子13内核苷酸A／G多态性与帕金森病(Parkinson’s disease，PD)遗传易患性的关系。方法 利用聚合酶链反应—变性高压液相技术(PCR—DHPLC)分析了MAO—B基因13内含子A／G多态性在PD患者与健康对照之问分布频率的差异。结果 野生基因型(A或AA)在总体PD或对照组中的分布频率77．8％和74．0％，杂合基因型A／G的频率分别为11．7％和8．4％；突变基因型(G／G或G)分别为10．5％和17．5％，使患PD的危险度降低1．8倍(P=0．04)；按发病年龄分组，突变基因型使患者早发PD的危险度降低2．4倍(P=0．031)。无论从总体分析，还是按发病年龄或性别分组，等位基因在各个组的分布频率差异无显著意义。结论 MAO—B的A／A(A)基因型是PD发生的危险因素，与PD的遗传易患性有关，对早发PD影响较大。     

VPS35 gene variants are not associated with Parkinson's disease in the mainland Chinese population

VPS35 gene mutation has recently been reported in autosomal-dominant, late-onset Parkinson disease (PD). There are no reports regarding the association between VPS35 and Parkinson's disease (PD) in the Chinese population. We conducted a comprehensive genetic analysis of VPS35 gene in a cohort of twenty seven probands belonging to families with autosomal-dominant, late-onset PD, followed up with screening of specific variants in a separate group of 1011 sporadic PD patients and 1016 healthy controls. Our analysis revealed two exonic variants and three intronic variants across the entire VPS35 gene. There was no statistical difference in genotype or allele frequencies of rs3743928 and IVS14?24 t > c variants in VPS35 gene between sporadic PD group and healthy control group. None of the 1011 sporadic PD patients and 1016 controls carried the VPS35 gene c.1858G > A (p.Asp620Asn) mutation. Our data indicated that the VPS35 variants are not associated with PD in the mainland Chinese population.