Gene-environment interactions in parkinsonism and Parkinson’s disease: the Geoparkinson study

Abstract

Objectives:To investigate associations of Parkinson’s disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk.Methods:A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status.CYP2D6,PON1,GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX,DAT1, DRD2andNAT2were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders.Results:There was a modest but significant association betweenMAO-Apolymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects betweenGSTM1 nullgenotype and solvent exposure (which were stronger when limited to PD cases only).Conclusions:Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects.GSTM1 nullsubjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…A French study [274] reported that risk of PD for professional pesticide use was more than doubled in slow metabolizers compared to other individuals, whereas, in the absence of pesticide exposure, slow metabolizers had no increased risk [274]. These results were supported by an Australian study [275] but not by a European multicentre study [276].…”

Pharmacogenetics of antidepressant response

“…Variations in CYP2D6 have been associated with a vast list of diseases (e.g., arterial hypertension, 12 leukemia, 13 childhood apnea, 13 thyroid cancer, 14 Alzheimer disease and Parkinson disease, [15][16][17][18][19] hepatic disease, 20 pulmonary disease, 21,22 breast cancer, 23 porphyrias 24 ) and with people's ability to metabolize antidepressants. 25 To date, up to 75 different alleles have been reported for CYP2D6 (descriptions available at www .imm.ki .se/cypalleles); more than 15 of these encode an inactive isoform or no enzyme, whereas other variations consist of gene duplications.…”

Association of four GSTs gene polymorphisms with Parkinson disease: A meta-analysis

“…Among them, 17 studies [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] that met the inclusion criteria were involved in our meta-analyses. Among the involved studies, 3 studies for GSTP1-104 variant [26,29,31] were excluded for the deviation from HWE in controls (p < Figure 1.…”

“…GST enzymes can detoxify many oxidative products and thus lower the PD risk in the smokers [20] and the people with pesticides exposure [21]. GST genes that have been studied most in the PD association include GSTT1 [22][23][24][25][26][27][28][29][30][31][32][33] on chromosome 22q11.23, GSTM1 [22][23][24][25][26][27][28]30,[32][33][34][35][36][37][38] on chromosome 1p13.3, and GSTP1 [23,26,[28][29][30][31]33,37,38] on chromosome 11q13. The phenotypic absence of GSTM1 and GSTT1 activity is the consequences of homozygous deletion of these genes [39,40].…”