Paola Costa-Mallen

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 Parkinsons 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.

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 Parkinsons 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.

Modulation of DNA synthesis by muscarinic cholinergic receptors

Abstract 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.

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 Parkinsons disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinsons disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinsons 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 Parkinsons 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 Parkinsons disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinsons 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 Parkinsons disease.

The functional polymorphism of the hemoglobin‐binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease

Oxidative stress and iron have been widely implicated in the etiology of Parkinsons disease (PD). Hemoglobin is the richest source of iron in the body. The human Haptoglobin (Hp) protein is a plasma alpha‐2 glycoprotein that removes free Hemoglobin from the circulation and tissues and is important in protection from oxidative stress, in immune system regulation, and angiogenesis. A common genetic polymorphism of Hp exists in the population, where the Hp 1‐1, Hp 2‐1, and Hp 2‐2 forms exhibit profound functional differences. In this study, the Hp genotype corresponding to phenotypes Hp 1‐1, 2‐1 and 2‐2 was determined in 312 idiopathic PD patients and 420 normal control subjects. A significant increase in the number of subjects carrying the Hp 2‐1 genotype was present among PD patients. The distribution of Hp genotypes among PD patients (16.0% Hp 1‐1, 56.4% Hp 2‐1, 27.6% Hp 2‐2) was significantly different from the distribution in controls (15.2% Hp 1‐1, 48.1% Hp 2‐1, 36.7% Hp 2‐2) (χ2 = 6.99, P = 0.030). The odds ratios for PD risk for Hp 2‐1 and Hp 1‐1 versus Hp 2‐2 genotype were 1.51 (1.07–2.12) and 1.36 (0.86–2.15), respectively. Overall, the association of Hp‐1 allele with PD resulted stronger among subjects who were never‐smokers as compared to ever‐smokers. Also, among ever‐smokers, Hp genotypes were significantly associated with PD only among women, but not men, indicating the presence of a gene × gender × smoking interaction. To our knowledge, this is the first study that investigates the association of Hp genotypes with the risk of PD.

Genotype combinations for monoamine oxidase-B intron 13 polymorphism and dopamine D2 receptor TaqIB polymorphism are associated with ever-smoking status among men

Tobacco smoke inhibits monoamine oxidase-B (MAO-B) activity in vitro and in vivo, suggesting that MAO-B inhibition is a possible contributing factor to tobacco smoke addiction. Thus, MAO-B is a possible candidate gene for predisposition to smoking. The TaqIB polymorphism for the Dopamine D2 Receptor gene (DRD2) has been previously associated with smoking status, although with some contradictory results. We investigated whether genetic variants of MAO-B intron 13 and DRD2 TaqIB polymorphism could be associated with smoking status among control subjects. There was no association of the intron 13 polymorphism itself with smoking status in either men or women. Similarly, no association with smoking status was observed for the TaqIB polymorphism of DRD2 itself. However, among men, there was an interaction between MAO-B intron 13 polymorphism and the DRD2 TaqIB polymorphisms, in which subjects carrying MAO-B allele A and genotype B12 of DRD2 were 2.50 times (95% CI=1.05-5.95) more likely to be ever-smokers than the pool of men carrying all other genotype combinations. These results demonstrate that particular combinations of genotypes for MAO-B and DRD2 genes are associated with significantly higher risk for smoking behavior in men, but not in women.

Paraoxonase 1 promoter and coding region polymorphisms in Parkinson’s disease

Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. Epidemiological studies have found associations of PD with pesticide exposure, or suspected pathways of pesticide exposure, such as rural residence and well water consumption. Many organophosphorous insecticides (for example, chlorpyrifos and diazinon) are bioactivated to potent cholinesterase inhibitors by the cytochromes P450, and the resulting toxic oxon forms are hydrolysed by paraoxonase (PON1). Genetic variants of detoxifying enzymes or pesticide metabolising enzymes, such as paraoxonase, may confer a predisposition to PD and thus are considered candidate genes for association studies. Multiple polymorphisms have been identified in the PON1 gene. The coding region contains two common polymorphisms, at amino acid codons 55 and 192. The glutamine (Q) to arginine (R) substitution at codon 192 causes substrate dependent differences in the kinetics of hydrolysis: compared with the PON1 192Q isoform, PON1 192R has higher activity towards paraoxon and chlorpyrifos oxon, but lower activity towards diazoxon, soman, and sarin. The leucine (L) to methionine (M) substitution at codon 55 does not affect the catalytic efficiency of substrate hydrolysis by the enzyme, but the PON1 55M allele is correlated with decreased mRNA and protein levels, because of linkage disequilibrium with a single nucleotide polymorphism (SNP) at position -108 of the promoter region of the gene. Five SNPs have been identified …

Haptoglobin phenotype modifies serum iron levels and the effect of smoking on Parkinson disease risk

INTRODUCTION Haptoglobin is a hemoglobin-binding protein that exists in three functionally different phenotypes, and haptoglobin phenotype 2-1 has previously been associated with Parkinson disease (PD) risk, with mechanisms not elucidated. Some evidence is emerging that low levels of serum iron may increase PD risk. In this study we investigated whether PD patients have lower serum iron and ferritin than controls, and whether this is dependent on haptoglobin phenotype. We also investigated the effect of Hp phenotype as a modifier of the effect of smoking on PD risk. METHODS The study population consisted of 128 PD patients and 226 controls. Serum iron, ferritin, and haptoglobin phenotype were determined, and compared between PD cases and controls. Stratified analysis by haptoglobin phenotype was performed to determine effect of haptoglobin phenotype on serum iron parameter differences between PD cases and controls and to investigate its role in the protective effect of smoking on PD risk. RESULTS PD cases had lower serum iron than controls (83.28 ug/100 ml vs 94.00 ug/100 ml, p 0.006), and in particular among subjects with phenotype 2-1. The protective effect of smoking on PD risk resulted stronger in subjects with phenotype 1-1 and 2-2, and weakest among subjects with phenotype 2-1. Ferritin levels were higher in PD cases than controls among subjects of White ethnicity. CONCLUSIONS Our results report for the first time that the haptoglobin phenotype may be a contributor of iron levels abnormalities in PD patients. The mechanisms for these haptoglobin-phenotype specific effects will have to be further elucidated.

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 Parkinsons (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.

DNA sequence analysis of monoamine oxidase B gene coding and promoter regions in Parkinson's disease cases and unrelated controls

The allele G of the intron 13 G/A polymorphism of the monoamine oxidase B gene (MAO‐B) has been associated with Parkinsons disease (PD) in several studies. Apart from a potential direct effect on splicing processes, the association of this intronic polymorphism with PD is due possibly to linkage disequilibrium with other mutations in the coding or promoter regions of the gene. We addressed this latter hypothesis by determining the DNA sequence of the entire MAO‐B coding region comprising 15 exons and partial intronic sequences flanking each exon, in 33 cases with idiopathic PD and 38 unrelated controls. The promoter region of MAO‐B gene up to base −1,369 from ATG (start point of mRNA translation) was also sequenced to identify variants with potential functional effects on gene transcription. In the promoter region, a new polymorphism consisting of a C to T single base change was detected in position −1,114 from ATG, with an allelic frequency of 3.5%, but it was not associated with PD risk. No commonly occurring (>10%) polymorphisms were found in the exons or the intronic sequences flanking the exons, although several rare variants were detected in the coding and promoter regions.