Genetic and lifestyle risk factors and parkinson's disease : the dopamine connection.

Abstract

Among the neurodegenerative disorders identified to date, Parkinson's disease (PO) is the second most frequent disorder, after Alzheimer's disease. Although the first records date back to 1817, there is little data about PO etiology. In this study, a candidate gene approach was applied in a case-control study using 178 cases and 402 controls collected from the Maltese population as part of the EU funded FP5 Geoparkinson study. Genetic and environmental risk factors which together or individually may lead to disease pathogenesis were investigated. Mutations in known PO-causing genes namely Leucine Rich Repeat Kinase 2 (LRRK2) (LRRK2 G2019S and LRRK2 R1441G) and Alpha-synuclein (SNCA) (SNCA G209A) were tested in cases only. None of the cases had the LRRK2 R1441G or SNCA G209A mutations however an allele frequency of 1.4% was obtained for the LRRK2 G2019S mutation which may have implications in genetic testing. These however explain only a few proportions of all PO cases. Therefore candidate genes selected on the potential for their involvement in the pathophysiology of dopaminergic systems were studied focusing on mutations and polymorph isms known to exist in the Maltese population. These include Quinoid Dihydropteridine Reductase (QOPR) G230, Sepiapterin Reductase (SR) IVS2-2A>G, which are known to cause tetrahydrobiopterin (BH4) deficiencies and Methylenetetrahydrofolate Reductase (MTHFR) A1298C and C677T. The allele frequencies obtained were 0.3% for both cases and controls tested for QDPR G230 and 0.7% for the SR IVS2-2A>G in controls. The odds ratios for the MTHFR 677 CT genotype and IT genotype were OR 1.0 (95% CI 0.7-1.6) and OR 0.9 (95% CI 0.5-1.6) whilst for the MTHFR 1298, the odds ratios for the AC and CC genotypes were OR 1.1 (95% CI 0.7-1.7) and OR 1.2 (95%CI 0.6-2.1) respectively. None of these variants were found to be contributors to PD. Tobacco use (especially before PO symptom onset), coffee consumption, and beer and spirit consumption were found to be protective for PO whilst antidepressants, anxiolytics and hypnotics showed an increased odds ratios. Since there may be overlap between the etiologies of PO and substance use, an analysis of genes that can influence substance use was performed in controls only. Possible associations between smoking and the dopamine transporter (OAT1), dopamine receptor 02 (OR02A) and Cytochrome P450 lBl (CYP1Bl) genes, antidepressants and CYP1B1, alcohol and the Glutathione-S-transferase (GSTM3), Microsomal Epoxide Hydrolase (EPHX1) and N-acetyltransferase 2 (NAT2) genes were observed in the Maltese control samples and confirmed in other Geoparkinson countries.