ASSOCIATION OF SLOW ACETYLATOR GENOTYPE FOR N-ACETYLTRANSFERASE-2 WITH FAMILIAL PARKINSONS-DISEASE

Background Epidemiological studies have identified positive family his tory and exposure to environmental toxins as risk factors for Parkinso n's disease (PD). An inherited defect of xenobiotic metabolism could r esult in increased susceptibility to such toxins. We investigated the frequency of functionally relevant polymorphisms in six detoxification enzymes among patients with PD to elucidate the relation between thes e polymorphisms and the disease. Methods We obtained brain-tissue samp les from 100 patients with apparently sporadic PD and blood samples fr om 100 living patients with familiar PD. For the control group, we ext racted DNA from the tissue of 100 pathologically normal brains. The si x enzymes analysed in these three groups were: CYP2D6, CYP2E1, NAD(P)H -menadione reductase, glutathione transferases M1 and T1, and N-acetyl transferase 2. We also investigated N-acetyltransferase 2 in 100 blood samples from patients with genetically proven Huntington's disease. W e used PCR-based methods and restriction-enzyme analysis to detect pol ymorphisms. Findings The slow acetylator genotype for N-acetyltransfer ase 2 was more common in the familial PD group (69%) than in all contr ols (37%). Even after correction for multiple comparisons, this result remained highly significant (p=0.002) for familial PD compared with n ormal controls (odds ratio 3.79 [95% CI 2.08-6.90]) and compared with Huntington's disease (2.45 [1.37-4.38], p=0.004). The slow acetylator frequency for N-acetyltransferase 2 for sporadic PD was between that f or Huntington's disease and familiar PD. The frequencies of all the ot her polymorphisms were similar in the two study groups and the normal control group. Interpretation We found an association between the slow acetylator genotype for N-acetyltransferase 2 and familial PD. Furthe r studies are needed to investigate the biological relevance of these findings, but slow acetylation could lead to impaired ability of patie nts with familial PD to handle neurotoxic substances.