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 in PD, and perform meta-analysis of individual gene polymorphism. Methods: The 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. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. Results: The authors identified 84 studies on 14 genes, including dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), monoamine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acetyltransferase 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. Conclusion: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNA(Glu). Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.