MAOB intron 13 and COMT codon 158 polymorphisms, cigarette smoking, and the risk of PD.

BACKGROUND: A polymorphism (G to A transition) in intron 13 of the mitochondrial enzyme monoamine oxidase B (MAOB) gene may modify, alone or by interacting with the catechol-O-methyltransferase (COMT(LL)) genotype (low enzymatic activity), the risk of idiopathic PD. Also, the association between never smoking and PD risk may be present only in people with the MAOB G allele. METHODS: The authors studied two ongoing prospective cohorts-the Nurses' Health Study (121,700 women aged 30 to 55 in 1976) and the Health Professionals' Follow-up Study (51,529 men aged 40 to 75 in 1986). They identified new PD cases through 1996, selected random control subjects matched on age and study cohort, and obtained DNA samples from blood or buccal smears from 85% of the eligible cases and 84% of the control subjects. They included genotypes from 214 cases and 449 control subjects, all Caucasian. RESULTS: The odds ratio of PD was 1.2 (95% CI 0.9, 1.7) for MAOB genotypes G/GG/GA compared with genotypes A/AA, and 1.1 (0.7, 1.8) for COMT genotypes LL compared with HH. The odds ratio (95% CI) was 1.7 (0.7, 3.9) for those with MAOB G/GG and COMT(LL) genotypes compared with those with MAOB A/AA and COMT(HH). There was a strong association between never smoking and PD risk in all groups defined by MAOB and COMT genotypes. CONCLUSION: The findings do not support a major role of the MAOB intron 13 polymorphism in the development of PD, either by itself or by interacting with smoking.

A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease.

In a population-based case-control study, we found a reversal of the association of cigarette smoking with Parkinson's disease (PD) in relation to the monoamine oxidase B intron 13 genetic polymorphism. A reduced PD risk related to pack-years of smoking was detected for persons with the G allele, whereas an opposite effect was found among persons with the A allele. These results indicate an unexplained interaction between cigarette smoking and this genetic polymorphism.

Interaction of blood lead and delta-aminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead smelter workers.

The gene that encodes gamma-aminolevulinic acid dehydratase (ALAD) has a polymorphism that may modify lead toxicokinetics and ultimately influence individual susceptibility to lead poisoning. To evaluate the effect of the ALAD polymorphism on lead-mediated outcomes, a cross-sectional study of male employees from a lead-zinc smelter compared associations between blood lead concentration and markers of heme synthesis and semen quality with respect to ALAD genotype. Male employees were recruited via postal questionnaire to donate blood and urine for analysis of blood lead, zinc protoporphyrin (ZPP), urinary coproporphyrin (CPU), and ALAD genotype, and semen samples for semen analysis. Of the 134 workers who had ALAD genotypes completed, 114 (85%) were ALAD1-1 (ALAD1) and 20 (15%) were ALAD1-2 (ALAD2). The mean blood lead concentrations for ALAD1 and ALAD2 were 23.1 and 28.4 microg/dl (p = 0.08), respectively. ZPP/heme ratios were higher in ALAD1 workers (68.6 vs. 57.8 micromol/ml; p = 0.14), and the slope of the blood lead ZPP linear relationship was greater for ALAD1 (2.83 vs. 1.50, p = 0.06). No linear relationship between CPU and blood lead concentration was observed for either ALAD1 or ALAD2. The associations of blood lead concentration with ZPP, CPU, sperm count, and sperm concentration were more evident in workers with the ALAD1 genotype and blood lead concentrations >/= 40 microg/dl. The ALAD genetic polymorphism appears to modify the association between blood lead concentration and ZPP. However, consistent modification of effects were not found for CPU, sperm count, or sperm concentration.

The EcoRV genetic polymorphism of human monoamine oxidase type A is not associated with Parkinson's disease and does not modify the effect of smoking on Parkinson's disease.

We previously observed an association with Parkinson's (PD), and modification of the effect of smoking on PD, by a polymorphism of the monoamine oxidase B (MAO-B) gene. The A form of monoamine oxidase (MAO-A) shares with MAO-B many characteristics that could be relevant to PD, especially proneuroxicant bioactivation and dopamine metabolism. MAO-A is also inhibited by tobacco smoke, which bears an apparent protective effect on PD. We investigated the possibility that MAO-A genetic variants may also be involved in predisposition to PD and in modification of the effect of smoking. Three-hundred and seventy-one subjects--145 idiopathic PD cases and 226 age/gender-matched controls--were genotyped for the EcoRV polymorphism of MAO-A gene which has been related to increased enzyme activity. MAO-A EcoRV polymorphism was neither significantly associated with PD nor did it modify the inverse relationship with smoking. These results suggest that the EcoRV polymorphism of MAO-A is not an important biomarker of PD risk.

Genetic polymorphisms in Parkinson's disease.

The search for genetic polymorphisms relevant to Parkinson's disease etiology and pathogenesis has been motivated by recent thinking emphasizing the potential significance of gene-environment interactions. Especially influential to this research have been the MPTP model of PD induction, hypotheses concerning oxidative stressor reactions, and epidemiological observations of an inverse relation between cigarette smoking and PD risk. This brief review summarizes trends in genetic polymorphism research, with examples provided by investigations of cytochrome P450 enzymes, monoamine oxidase, superoxide dismutase, and mitochondrial genes.

Mitochondrial ND1 sequence analysis and association of the T4216C mutation with Parkinson's disease.

Mitochondrial dysfunction originating from mutations in Complex I genes may play a role in the pathogenesis of Parkinson's disease (PD). In this study, the entire ND1 coding sequence was sequenced in 84 newly diagnosed PD cases and 127 age/gender-matched controls. Numerous missense mutations were found at low frequency (<5%), whereas a thymidine to cytosine missense mutation at position 4216 that results in the replacement of tyrosine with histidine was found in 25% of the PD case samples and in 18% of the controls. When calculated according to gender, the 4216 mutation was observed in 26% of the male cases versus 16% of male controls (Odds Ratio [OR] = 1.85; 95% CI = 0.79-4.34). In contrast, females exhibited approximately equal frequencies among cases (22.5%) and controls (21%), yielding an OR of 1.08 (95% C.I. = 0.36-3.22). The findings indicate only a weak association of this genetic variant with PD.

Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism.

Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.

Modulation of DNA synthesis by muscarinic cholinergic receptors.

Acetylcholine muscarinic receptors are a family of five G-protein-coupled receptors widely distributed in the central nervous system and in peripheral organs. Activation of certain subtypes of muscarinic receptors (M1, M3, M5) has been found to modulate DNA synthesis in a number of cell types. In several cell types acetylcholine, by activating endogenous or transfected muscarinic receptors, can indeed elicit cell proliferation. In other cell types, however, or under different experimental conditions, activation of muscarinic receptors has no effect, or inhibits DNA synthesis. A large number of intracellular pathways are being investigated to define the mechanisms involved in these effects of muscarinic receptors; these include among others, phospholipase D, protein kinases C and mitogen-activated-protein kinases. The ability of acetylcholine to modulate DNA synthesis through muscarinic receptors may be relevant in the context of brain development and neoplastic growth.