N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson's disease

Abstract

Background: Parkinson's disease (PD) is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The molecular basis of this neural death is unknown, but genetic predisposition and environmental factors may cause the disease. Sequence variations in N-acetyltransferase 2 (NAT2) gene leading to slow acetylation process have been associated with PD, but results are contradictory.

Methods: We analyzed three NAT2 genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects and 124 PD patients for these genetic variations. Further, we have undertaken a systematic review of NAT2 studies on PD and we incorporated our results in a meta-analysis consisting of 10 studies, 1,206 PD patients and 1,619 control subjects.

Results: Overall, we did not find significant differences in polymorphic acetylation genotypes in PD and control subjects. In the meta-analysis of slow acetylators from 10 studies and representing 604/1206 PD vs. 732/1619 control subjects, a marginally significant odds ratio (OR) of 1.32 (95% CI 1.12-1.54, p < 0.05) was obtained. Re-analysis of the data to exclude the only two studies showing positive association of slow acetylators to PD, resulted in a non-significant OR (1.07, 95% CI 0.9-1.28). Furthermore, meta-analysis of studies for c.590G>A, where both allele and genotype frequencies in PD vs. control subjects were analyzed, did not give significant summary odds ratios as well.

Conclusion: We found little evidence for differences in polymorphic acetylation genotypes in PD and control subjects. Results of the meta-analyses did not also provide conclusive evidence for an overall association of NAT2 slow acetylator genotypes to PD.

Figure 1

Meta-analysis of association studies on NAT2 slow acetylators and sporadic Parkinson's disease. The confidence interval for each study is given by a horizontal line, and the point estimate is given by a square whose height is inversely proportional to the standard error of the estimate. The summary odds ratio is drawn as a diamond with horizontal limits at the confidence limits and width inversely proportional to its standard error. (A): Meta-analysis on 10 studies. Test for heterogeneity χ² (df 9) = 47.71 (p-value 0). The odds ratios are significantly different between the studies. The summary odds ratio (Mantel-Haenszel OR= 1.32, 95% CI, 1.12–1.54) is significantly greater than 1 (p < 0.05). (B) Meta-analysis on 8 studies, excluding studies of Bandmann et al. 2000 and Chan et al. 2003. The odds ratios are not significantly different between studies. Test for heterogeneity χ² (df 7) = 14.28 (p = 0.0464). The summary odds ratio (OR= 1.07, 95% CI, 0.9–1.28) is not significant.

Figure 2

Meta-analysis of NAT2 c.590G>A in PD and control subjects. The confidence interval for each study is given by a horizontal line, and the point estimate is given by a square whose height is inversely proportional to the standard error of the estimate. The summary odds ratio is drawn as a diamond with horizontal limits at the confidence limits and width inversely proportional to its standard error. Allele frequency: Test for heterogeneity χ² (df 4) = 2.36 (p-value 0.67). The odds ratios are not significantly different between the studies (p = 0.67). The summary odds ratio (Mantel-Haenszel OR= 0.94, 95% CI, 0.79–1.12) is not significantly greater than 1 (p > 0.05). Genotype frequency: Test for heterogeneity χ² (df 3) = 9.58 (p-value 0.0225). The odds ratios are not significantly different between the studies (p = 0.0225). The summary odds ratio (Mantel-Haenszel OR= 0.94, 95% CI, 0.78–1.43) not significantly different from 1.