Variability and validity of polymorphism association studies in Parkinson's disease

Background: In recent years, interest in gene-environment interactions has spurred a great number of association studies on polymorphism of different genes. Objective: To review case-control studies of genetic polymorphisms i n PD, and perform meta-analysis of individual gene polymorphism. Methods: T he authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD . The key words used were "PD" and "polymorphism." The authors supplemented the search with relevant references quoted in these published articles. Th ose with four or more independent studies of a specific gene polymorphism w ere subjected to meta-analysis, with the exception of cytochrome-P450 enzym e polymorphisms, for which meta-analyses results were already available in the literature. Results: The authors identified 84 studies on 14 genes, inc luding dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), mono amine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acety ltransferase 2 (NAT2), APOE, glutathione transferase (GSTT1, GSTM1, GSTP1, and GSTZ1), and mitochondrial genes (tRNA(Glu) and ND2). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)(n) polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNA(Glu) (OR = 3.0). No significant differences were found for the other genes. Conc lusion: Significant associations with PD were found in polymorphisms of NAT 2, MAOB, GSTT1, and tRNA(Glu). Although significant association does not im ply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further .