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Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study



There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4-hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP.


DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.


The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).


Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.

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Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Classically, patients present with progressive postural instability and falls followed by slow and hypometric vertical saccades and eventually vertical supranuclear gaze palsy.

Neuropathologically, PSP is characterized by deposits of four-repeat microtubule associated protein tau (encoded by the MAPT gene) aggregates in neurons and glia of the basal ganglia and brain-stem [1]. Additionally, there is mitochondrial dysfunction, decreased ATP levels and inflammation in the brains of PSP patients [24]. The MAPT H1 haplotype has been consistently reported to be associated with PSP; however, it is also common in the general population, suggesting that gene-gene or gene-environment interactions are likely required for the development of this disease [5, 6]. Recently, MAPT H1 was also associated with risk of Parkinson's disease (PD) suggesting shared pathways of disease [7]. Early-onset PD and PSP can present with a similar phenotype and be misdiagnosed, supporting common links between the two disorders. The product of PTEN-induced putative kinase (PINK1, PARK6), associated with early-onset PD, is involved in mitochondrial respiration and protection from oxidative damage, which are pathways that have also been linked to risk of PSP [813]. PINK-1 polymorphisms are also associated with PD and it acts in conjunction with parkin to regulate mitochondrial functioning. Although the mechanisms by which PINK1 acts are not fully understood; research suggests that it is crucial for healthy mitochondrial respiration and ATP production [8]. Considering the role of PINK1 in mitochondrial functioning along with its previous links to PD, specific PINK1 SNPs were included in this study to determine if there is also an association with PSP.

Consumption of annonaceous fruit and teas, which contain mitochondrial inhibitors, has been associated with an atypical parkinsonian disorder similar to PSP in the French West Indies [14, 15]. Considering that mitochondrial impairment is observed in PSP brains, mitochondrial complex-1 inhibitors and other chemical neurotoxins, such as organophosphates, are hypothesized as risk factors for PSP [1618]. These and other potentially toxic compounds are metabolized by the products of several genes: debrisoquine 4-hydroxylase (CYP2D6), paraoxonase (PON) 1 and 2, N-acetyltransferase (NAT) 1 and 2, and superoxide dismutase (SOD) 1 and 2 [1013, 1922]. CYP2D6 is found in the brain and is involved in metabolism of MPTP, herbicides (paraquat) and organophosphate pesticides [11, 12]. Reduced in 5-10% of Caucasians, genetic polymorphisms of this enzyme have been widely studied in PD and results suggest that there is an association of the poor metabolizer phenotype with disease development [23, 24]. Moreover, the combination of pesticide exposure and CYP2D6 poor metabolizer phenotype doubles PD risk [11, 20]. PON1 hydrolyzes phosphoric acid esters, organophosphates and aromatic carboxylic acid esters and blocks the formation of free radicals. With low PON1 activity, these pesticides are not metabolized and the cell is subject to increased oxidative stress [19]. The PON 1 M allele, which is correlated with decreased protein levels, has been shown to be associated with PD [25, 26] and the M/M genotype was recently reported to be associated with early onset PD [27]. Additionally, decreased PON1 activity was overrepresented in PD patients from agriculturally exposed areas [19]. NAT1 and NAT2 are involved in the biotransformation of drugs and environmental toxins (xenobiotics) [28]. These enzymes transfer the acetyl group from acetyl-coenzyme A (acetyl CoA) to an amino group on aromatic amines and hydrazine compounds. In addition, following N-hydroxylation, they can further activate xenobiotics via O-acetylation [29]. There are a number of SNPs reported in NAT1 and NAT2, which lead to slow and rapid acetylator phenotypes. The acetylation status of an individual might determine how they respond to xenobiotic exposures, therefore presenting the NAT genes as candidates for gene-environment interaction studies. The slow acetylator phenotype is reported to be associated with PD, but inconsistent results warrant further investigation [3034]. SOD is an important antioxidant enzyme, which converts superoxide anions (O2-) to hydrogen peroxide (H2O2). Considering the antioxidant properties of the enzyme, polymorphisms resulting in decreased SOD activity would be expected to have detrimental effects on the cell; however, recent studies suggest the opposite is true [3537]. The mechanism behind this gain of function toxicity remains unknown, but it is proposed to be a result of either 1) disrupting the balance of O2- and H2O2, or 2) self-aggregation. Numerous SOD polymorphisms have been found to be associated with amyotrophic lateral sclerosis (ALS) [38], and may play a role in PD and AD pathogenesis [39].

To determine if genetic polymorphisms in toxicant metabolism increases risk for developing PSP, we investigated associations between PSP and specific single nucleotide polymorphisms (SNPs) in the aforementioned genes.



DNA samples from 545 autopsy-confirmed PSP cases collected between 1993 and 2008 at the PSP Society Brain Bank were included [40]. All cases were from the US and Canada. Control DNA samples (n = 426) were randomly selected from an existing repository of control samples at the Mayo clinic, Jacksonville. All controls were healthy spouses or caregivers of patients at the Mayo Clinic in Jacksonville, FL and free from neurological disorders. All samples were from adults over the age of 33 (see Table 1 for demographic information). Institutional review board (IRB)-approved protocols, including informed consent, were followed to obtain all DNA samples.

Table 1 Characteristics of PSP Cases and Controls


Within 48 hours of collection, DNA was extracted by standard protocols and stored at -80°C until used. NAT1 (rs4987076, rs5030839, rs4986782, rs1057123, and rs15561) and NAT2 (rs1208, rs1801279, rs1801280, rs1799929, rs1799930, rs1799931, and rs1041983) genotyping was performed using Taqman PCR methodology on an ABI Prism 7700 sequence detection system as previously published [41, 42]. All other genotyping was performed on a Sequenom Mass Array iPLEX platform using the Gold Assay (San Diego, CA) as described previously [43] (see Table 2 for rs numbers). Primer sequences are available upon request. The rs numbers tested here also included in the recent GWAS on PSP are rs1043424, rs662, rs7493, rs1801280, rs1799930, rs1799931, rs1799929, and rs1041983 [44].

Table 2 Case-control comparison of SNP genotypes

Data analysis

Statistical analyses were performed using R software (R Development Core Team 2009). Chi-squared, Fisher's exact, student t-test, or Wilcoxon rank sum analyses were used to test for differences in demographic variables between cases and controls. For each iPLEX SNP variable, the Cochran-Armitage and chi-squared tests were used to test additive, dominant, and recessive genetic models. In addition, logistic regression was used to test these same genetic models while adjusting for significant demographic variables (i.e. age). Logistic regression models were also used to determine whether specific NAT1 or NAT2 genotypes or NAT2 phenotypes were associated with PSP. NAT2 phenotypes may be accurately assigned according to genotype [22]; therefore, NAT2 analysis was initially restricted to phenotypic evaluation, which was followed by genotypic analysis. Overall significance of the associations was determined using the omnibus chi-squared test for the model. If the omnibus chi-squared test was not significant, then individual genotypes were not considered significant even if the associated p-value (p) was < 0.05. Odds ratios (OR), 95% confidence intervals (CI) and p-values were determined for each variable. Associations with p < 0.05 were considered significant. Based on the outcome of the primary analysis, t-test or Wilcoxon rank sum test was applied to determine whether means/medians were different between NAT2 phenotypes for age at onset, age at death or disease duration in cases. NAT2 genotype, NAT1 genotype and iPLEX SNP associations were all tested independently each with either a large number of groups or a low number of tests; nevertheless, when p-values were less than 0.05, adjustments were made for multiple testing using the Holm correction [45]. NAT2 phenotype tests were modeled independently from SNP analyses. Furthermore, while multiple SNPs were determined to input the phenotypes, only two phenotypes were compared (i.e. rapid versus slow/intermediate), therefore no multiple testing correction was needed as previously described for testing the NAT2 phenotype association with colorectal cancer [46].


On average, cases were older than controls at sample collection time (Table 1, p < 0.001), with age at collection time for PSP cases being age at death. Trend analysis of the iPLEX SNPs showed no between-group differences in genotypes (Table 2), with the exception of rs1052553 (MAPT H1 OR = 4.35, CI = 3.08-6.25, p < 0.001), which is a known association [47]. Each marker was confirmed to be in Hardy-Weinberg equilibrium in controls. Minor allele frequencies (MAFs) for rs numbers 1043424 and 705381 were higher in both our PSP and control populations compared to that reported for the general (Caucasian) population. For rs numbers 4880 and 1052553 only the PSP sample differed from the general population (Table 3). There were no between-group differences for NAT1 genotypes (Table 4). NAT2 slow and intermediate phenotypes did not differ between groups (p = 0.96), thus these groups were combined and compared against the rapid phenotype for further analyses. Phenotypic analysis showed cases had a significantly higher proportion of NAT2 rapid acetylators (OR = 1.82, CI = 1.05-3.28, p = 0.037) compared to intermediate and slow (Table 5). The omnibus chi-squared test for NAT2 genotypes was not significant (Table 6). Since NAT2 rapid phenotype was associated with PSP, rank sum analyses were used to determine whether NAT2 acetylation status predicted either age at onset or disease duration. NAT2 phenotype was not associated with age at onset or age at death. For disease duration the overall test was also not significant; however, individual pairwise comparisons for disease duration using a t-test (unequal variances, Table 7) corroborated results for association of NAT2 rapid phenotype with disease (Table 5). For example, mean disease duration was shorter for rapid NAT2 phenotype (6.6 yrs.) compared to slow (7.5 yrs. p = 0.025).

Table 3 Allele Frequencies of SNPs vs. General Population
Table 4 Case-control comparison of NAT1 genotypes
Table 5 Comparisons Between NAT2 Phenotypes
Table 6 Case-control comparison of NAT2 genotypes
Table 7 Survival of PSP cases by NAT2 phenotype


Our primary analysis revealed that none of the iPLEX SNPs was proportionally different between cases and controls except for MAPT rs1052553, which is a known association. On the other hand, significant differences were detected when comparing MAFs of cases with reported MAFs for the general population. There were no differences in NAT1 or NAT2 genotypes between cases and controls. NAT2 rapid acetylator phenotype was more frequent in PSP cases than controls while intermediate and slow acetylator phenotypes were less frequent in cases.

Although trend analysis did not show differences between cases and controls for the iPLEX SNPs (i.e. except for rs1052553), cases did differ from the general population (CEU) in some MAFs. Of particular interest is SOD2 rs4880, which differed from the general population in cases, but not controls. Though not conclusive, this suggests a possible association of rs4880 with PSP. The MAPT H1 allele is known to be associated with PSP; however, it is the major allele. Consistent with previous studies, we found that MAPT genotype and MAFs differed between PSP cases, with the H1 allele conferring risk [6, 44]. Furthermore, MAF comparisons indicate the H2 allele is protective, as it had a lower frequency in our cases compared to the general population (Table 3). Our results also suggest that NAT2 rapid acetylator status might increase risk for developing PSP. This is consistent with NAT2-catalyzed toxicant activation (perhaps via O-acetylation). Therefore, a higher rate of acetylation would result in a higher concentration of toxic metabolite in the system. NAT2 catalyzes the O-acetylation of N-arylhydroxylamines resulting in bioactivation [48].

This is an observational study, therefore more emphasis should be placed on the estimated odds ratio and precision of the confidence intervals rather than on p-values [49]. Nevertheless, these trends must be confirmed by additional studies. Our results did not provide statistical evidence for an effect of NAT2 phenotype on onset age, age at death or disease duration. In accord with our finding that NAT2 rapid phenotype is more frequent in cases than controls, pairwise comparisons did show a trend supporting a potential link between rapid phenotype and shorter disease duration (Table 7). It is important to note that this particular analysis may have been underpowered for detecting differences in the outcome parameters since the lack of disease onset and duration information for many cases substantially decreased the sample size.

Our findings are noteworthy as NAT2*4, which confers the rapid phenotype, was designated originally as the "wild-type" allele since it is common among many ethnic groups other than Europeans or Caucasians [29]. Although the frequency of NAT2*4 is not as common among Caucasians (which is the group analyzed in our study), this association may still be similar to the MAPT H1 haplotype association with PSP (i.e. MAPT H1 is associated with increased PSP risk, but is also very common in the general population with a frequency of 0.78) [6]. Therefore, even though our results suggest the rapid acetylator phenotype increases risk for PSP, this is only one of potentially numerous factors that converge to determine individual risk for disease. On the other hand, our finding is contrary to recent findings that NAT2 rapid acetylator genes enhance the protective effect of smoking in PD (De Palma et al. 2010) and reports suggesting that the NAT2 slow acetylator phenotype increases risk for PD [5052]. PSP is a tauopathy and PD is a synucleinopathy, thus, these are two distinct diseases that may have distinct pathogenic mechanisms and risk factors [53]. There are varying reports of NAT2 polymorphisms associating with PD, PSP, and AD. While many suggest that slow alleles or phenotypes increase disease risk [31, 32, 5052], others indicate increased risk with rapid or intermediate conferring genotypes and protection by slow alleles or genotypes [13, 54]. Still others suggest there are no links between these diseases and NAT polymorphisms [18, 30, 33, 55, 56]. In view of these conflicting reports on the role of NAT genetic polymorphisms in neurodegeneration together with our results, additional studies are needed to determine whether NAT alleles or genotypes conferring rapid acetylation increase risk for neurodegenerative diseases or if the slow alleles/genotypes are protective or vice versa.


The control series we used was more geographically confined than our PSP population and the CEU population from which the general population MAFs were derived. Interestingly, for some of the MAFs our control population differed from the general population. This could explain why our genotype comparisons between cases and controls were not significant. Therefore, MAF comparisons between our PSP sample and the general/CEU population augment our case-control analyses. The main strength of this study was the large sample of pathologically well-characterized PSP cases from a single center. On the other hand, the clinical information was not collected in a systematic or standardized manner and controls were clinical, not pathological controls. Considering that PSP is a relatively rare disease, a still larger sample size may be necessary to detect smaller, yet biologically significant differences and investigate interaction effects. Likewise, as 514 of the PSP cases analyzed here were also included in the GWAS, this finding should be confirmed in an independent cohort. Although these findings need to be replicated, this data provides useful information to guide future genetic studies on PSP as it indicates that NAT2 rapid acetylator status should be considered as a potential risk factor for PSP in studies investigating gene-gene and gene-environment interactions. Furthermore, our results are consistent with the recent genome-wide association study (GWAS) on PSP that did not find any associations with SNPs rs1043424, rs662, rs7493 or any individual NAT2 SNPs [44]. The NAT2rs numbers tested here and included in the recent GWAS on PSP are rs1801280, rs1799930, rs1799931, rs1799929, and rs1041983 [44]. Though we did not find an association with any individual NAT2 SNPs, when we used the SNPs to input NAT2 phenotype we observed a significant association between imputed rapid NAT2 acetylator phenotype and PSP. This result is important since this method of testing NAT2 phenotype association with disease has been shown to be more useful than looking at individual SNPs [57, 58]. Thus, our study is quite different from the GWAS, and with respect to NAT2, much more powerful in terms of biological plausibility. Additionally, this study reveals the odds ratios and confidence intervals for a number of biologically relevant SNPs that have not been previously investigated in association studies on PSP. Our results provide support for the multiple-hit hypothesis and demonstrate the multifaceted nature of identifying risk factors for neurodegenerative diseases such as PSP.


  1. 1.

    Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I: Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994, 44 (11): 2015-2019.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Albers DS, Beal MF: Mitochondrial dysfunction in progressive supranuclear palsy. NeurochemInt. 2002, 40 (6): 559-564.

    CAS  Article  Google Scholar 

  3. 3.

    Stamelou M, Pilatus U, Reuss A, Magerkurth J, Eggert KM, Knake S, Ruberg M, Schade-Brittinger C, Oertel WH, Hoglinger GU: In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy. J Cereb Blood Flow Metab. 2009, 29 (4): 861-870. 10.1038/jcbfm.2009.2.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Ishizawa K, Dickson DW: Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J NeuropatholExpNeurol. 2001, 60 (6): 647-657.

    CAS  Article  Google Scholar 

  5. 5.

    Bonifati V, Joosse M, Nicholl DJ, Vanacore N, Bennett P, Rizzu P, Fabbrini G, Marconi R, Colosimo C, Locuratolo N, et al: The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases. NeurosciLett. 1999, 274 (1): 61-65.

    CAS  Google Scholar 

  6. 6.

    Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999, 8 (4): 711-715. 10.1093/hmg/8.4.711.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, et al: Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol. 2011, 69 (5): 778-792. 10.1002/ana.22321.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Dodson MW, Guo M: Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease. CurrOpinNeurobiol. 2007, 17 (3): 331-337.

    CAS  Google Scholar 

  9. 9.

    Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J: PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. BiochemBiophys Res Commun. 2008, 377 (3): 975-980. 10.1016/j.bbrc.2008.10.104.

    CAS  Article  Google Scholar 

  10. 10.

    Fong CS, Cheng CW, Wu RM: Pesticides exposure and genetic polymorphism of paraoxonase in the susceptibility of Parkinson's disease. ActaNeurol Taiwan. 2005, 14 (2): 55-60.

    Google Scholar 

  11. 11.

    Mellick GD: CYP450, genetics and Parkinson's disease: gene × environment interactions hold the key. J Neural TransmSuppl. 2006, 70: 159-165. 10.1007/978-3-211-45295-0_25.

    CAS  Article  Google Scholar 

  12. 12.

    Costa C, Catania S, Silvari V: [Genotoxicity and activation of organophosphate and carbamate pesticides by cytochrome P450 2D6]. Giornaleitaliano di medicina del lavoroedergonomia. 2003, 25 (Suppl(3)): 81-82.

    Google Scholar 

  13. 13.

    Rocha L, Garcia C, de Mendonca A, Gil JP, Bishop DT, Lechner MC: N-acetyltransferase (NAT2) genotype and susceptibility of sporadic Alzheimer's disease. Pharmacogenetics. 1999, 9 (1): 9-15.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Champy P, Hoglinger GU, Feger J, Gleye C, Hocquemiller R, Laurens A, Guerineau V, Laprevote O, Medja F, Lombes A, et al: Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe. J Neurochem. 2004, 88 (1): 63-69.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Lannuzel A, Hoglinger GU, Verhaeghe S, Gire L, Belson S, Escobar-Khondiker M, Poullain P, Oertel WH, Hirsch EC, Dubois B, et al: Atypical parkinsonism in Guadeloupe: a common risk factor for two closely related phenotypes?. Brain. 2007, 130 (Pt 3): 816-827.

    Article  PubMed  Google Scholar 

  16. 16.

    Liang TW, Balcer LJ, Solomon D, Messe SR, Galetta SL: Supranuclear gaze palsy and opsoclonus after Diazinon poisoning. J NeurolNeurosurg Psychiatry. 2003, 74 (5): 677-679. 10.1136/jnnp.74.5.677.

    Article  Google Scholar 

  17. 17.

    Chapuis J, Boscher M, Bensemain F, Cottel D, Amouyel P, Lambert JC: Association study of the paraoxonase 1 gene with the risk of developing Alzheimer's disease. Neurobiol Aging. 2007

    Google Scholar 

  18. 18.

    Nicholl DJ, Bennett P, Hiller L, Bonifati V, Vanacore N, Fabbrini G, Marconi R, Colosimo C, Lamberti P, Stocchi F, et al: A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism. Neurology. 1999, 53 (7): 1415-1421.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Benmoyal-Segal L, Vander T, Shifman S, Bryk B, Ebstein RP, Marcus EL, Stessman J, Darvasi A, Herishanu Y, Friedman A, et al: Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease. FASEB J. 2005, 19 (3): 452-454.

    CAS  PubMed  Google Scholar 

  20. 20.

    Elbaz A, Levecque C, Clavel J, Vidal JS, Richard F, Amouyel P, Alperovitch A, Chartier-Harlin MC, Tzourio C: CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease. Ann Neurol. 2004, 55 (3): 430-434. 10.1002/ana.20051.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Jaarsma D, Haasdijk ED, Grashorn JA, Hawkins R, van Duijn W, Verspaget HW, London J, Holstege JC: Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol Dis. 2000, 7 (6 Pt B): 623-643.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Hein DW: N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene. 2006, 25 (11): 1649-1658. 10.1038/sj.onc.1209374.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    McCann SJ, Pond SM, James KM, LeCouteur DG: The association between polymorphisms in the cytochrome P-450 2D6 gene and Parkinson's disease: a case-control study and meta-analysis. J NeurolSci. 1997, 153 (1): 50-53.

    CAS  Google Scholar 

  24. 24.

    Singh M, Khanna VK, Shukla R, Parmar D: Association of polymorphism in cytochrome P450 2D6 and N-acetyltransferase-2 with Parkinson's disease. Dis Markers. 2010, 28 (2): 87-93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kelada SN, Costa-Mallen P, Checkoway H, Viernes HA, Farin FM, Smith-Weller T, Franklin GM, Costa LG, Longstreth WT, Furlong CE, et al: Paraoxonase 1 promoter and coding region polymorphisms in Parkinson's disease. J NeurolNeurosurg Psychiatry. 2003, 74 (4): 546-547. 10.1136/jnnp.74.4.546.

    CAS  Article  Google Scholar 

  26. 26.

    Carmine A, Buervenich S, Sydow O, Anvret M, Olson L: Further evidence for an association of the paraoxonase 1 (PON1) Met-54 allele with Parkinson's disease. MovDisord. 2002, 17 (4): 764-766.

    Google Scholar 

  27. 27.

    Duric G, Svetel M, Nikolaevic SI, Dragadevic N, Gavrilovic J, Kostic VS: Polymorphisms in the genes of cytochrome oxidase P450 2D6 (CYP2D6), paraoxonase 1 (PON1) and apolipoprotein E (APOE) as risk factors for Parkinson's disease. Vojnosanit Pregl. 2007, 64 (1): 25-30. 10.2298/VSP0701025D.

    Article  PubMed  Google Scholar 

  28. 28.

    Erlich PM, Lunetta KL, Cupples LA, Huyck M, Green RC, Baldwin CT, Farrer LA: Polymorphisms in the PON gene cluster are associated with Alzheimer disease. Hum Mol Genet. 2006, 15 (1): 77-85.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Boukouvala S, Fakis G: Arylamine N-acetyltransferases: what we learn from genes and genomes. Drug metabolism reviews. 2005, 37 (3): 511-564. 10.1080/03602530500251204.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Maraganore DM, Farrer MJ, Hardy JA, McDonnell SK, Schaid DJ, Rocca WA: Case-control study of debrisoquine 4-hydroxylase, N-acetyltransferase 2, and apolipoprotein E gene polymorphisms in Parkinson's disease. MovDisord. 2000, 15 (4): 714-719.

    CAS  Google Scholar 

  31. 31.

    Chan DK, Lam MK, Wong R, Hung WT, Wilcken DE: Strong association between N-acetyltransferase 2 genotype and PD in Hong Kong Chinese. Neurology. 2003, 60 (6): 1002-1005.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, Singh S, Muthane UB, Juyal RC: B KT: Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians. Pharmacogenet Genomics. 2005, 15 (10): 731-735. 10.1097/01.fpc.0000173485.59430.49.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Borlak J, Reamon-Buettner SM: N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson's disease. BMC Med Genet. 2006, 7: 30-

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Punia S, Das M, Behari M, Dihana M, Govindappa ST, Muthane UB, Thelma BK, Juyal RC: Leads from xenobiotic metabolism genes for Parkinson's disease among north Indians. Pharmacogenet Genomics. 2011, 21 (12): 790-797. 10.1097/FPC.0b013e32834bcd74.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Jaarsma D, Haasdijk ED, Grashorn JA, Hawkins R, van Duijn W, Verspaget HW, London J, Holstege JC: Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiology of disease. 2000, 7 (6 Pt B): 623-643.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Liu D, Bao F, Wen J, Liu J: Mutation of superoxide dismutase elevates reactive species: comparison of nitration and oxidation of proteins in different brain regions of transgenic mice with amyotrophic lateral sclerosis. Neuroscience. 2007, 146 (1): 255-264. 10.1016/j.neuroscience.2007.01.028.

    Article  PubMed  Google Scholar 

  37. 37.

    Zimmerman MC, Oberley LW, Flanagan SW: Mutant SOD1-induced neuronal toxicity is mediated by increased mitochondrial superoxide levels. Journal of neurochemistry. 2007, 102 (3): 609-618. 10.1111/j.1471-4159.2007.04502.x.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Naini A, Mehrazin M, Lu J, Gordon P, Mitsumoto H: Identification of a novel D109Y mutation in Cu/Zn superoxide dismutase (sod1) gene associated with amyotrophic lateral sclerosis. J NeurolSci. 2007, 254 (1-2): 17-21.

    CAS  Google Scholar 

  39. 39.

    Choi J, Rees HD, Weintraub ST, Levey AI, Chin LS, Li L: Oxidative modifications and aggregation of Cu, Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. The Journal of biological chemistry. 2005, 280 (12): 11648-11655. 10.1074/jbc.M414327200.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Josephs KA, Dickson DW: Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank. MovDisord. 2003, 18 (9): 1018-1026.

    Google Scholar 

  41. 41.

    Doll MA, Hein DW: Comprehensive human NAT2 genotype method using single nucleotide polymorphism-specific polymerase chain reaction primers and fluorogenic probes. Anal Biochem. 2001, 288 (1): 106-108. 10.1006/abio.2000.4892.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Doll MA, Hein DW: Rapid genotype method to distinguish frequent and/or functional polymorphisms in human N-acetyltransferase-1. Anal Biochem. 2002, 301 (2): 328-332. 10.1006/abio.2001.5520.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, et al: High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007, 39 (3): 347-351. 10.1038/ng1975.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, et al: Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011, 43 (7): 699-705. 10.1038/ng.859.

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Holm S: A Simple Sequentially Refective Multiple Test Procedure. Scandinavian Journal of Statistics. 1979, 6: 65-70.

    Google Scholar 

  46. 46.

    Le Marchand L, Hankin JH, Wilkens LR, Pierce LM, Franke A, Kolonel LN, Seifried A, Custer LJ, Chang W, Lum-Jones A, et al: Combined effects of well-done red meat, smoking, and rapid N-acetyltransferase 2 and CYP1A2 phenotypes in increasing colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2001, 10 (12): 1259-1266.

    CAS  PubMed  Google Scholar 

  47. 47.

    Russ C, Powell JF, Zhao J, Baker M, Hutton M, Crawford F, Mullan M, Roks G, Cruts M, Lovestone S: The microtubule associated protein Tau gene and Alzheimer's disease- an association study and meta-analysis. NeurosciLett. 2001, 314 (1-2): 92-96.

    CAS  Google Scholar 

  48. 48.

    Liu L, Von Vett A, Zhang N, Walters KJ, Wagner CR, Hanna PE: Arylamine N-acetyltransferases: characterization of the substrate specificities and molecular interactions of environmental arylamines with human NAT1 and NAT2. Chem Res Toxicol. 2007, 20 (9): 1300-1308. 10.1021/tx7001614.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Anderson DR, Link WA, Johnson DH, Burnham KP: Suggestions for presenting the results of data analyses. Journal of Wildlife Management. 2001, 65 (3): 373-378. 10.2307/3803088.

    Article  Google Scholar 

  50. 50.

    De Palma G, Dick FD, Calzetti S, Scott NW, Prescott GJ, Osborne A, Haites N, Mozzoni P, Negrotti A, Scaglioni A, et al: A case-control study of Parkinson's disease and tobacco use: gene-tobacco interactions. MovDisord. 25 (7): 912-919.

  51. 51.

    Bandmann O, Vaughan J, Holmans PA, Marsden CD, Wood NW: Toxins, genetics, and Parkinson's disease: the role of N-acetyltransferase 2. AdvNeurol. 1999, 80: 199-204.

    CAS  Google Scholar 

  52. 52.

    Grundmann M, Earl CD, Sautter J, Henze C, Oertel WH, Bandmann O: Slow N-acetyltransferase 2 status leads to enhanced intrastriatal dopamine depletion in 6-hydroxydopamine-lesioned rats. ExpNeurol. 2004, 187 (1): 199-202.

    CAS  Google Scholar 

  53. 53.

    Wider C, Vilarino-Guell C, Jasinska-Myga B, Heckman MG, Soto-Ortolaza AI, Cobb SA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, et al: Association of the MAPT locus with Parkinson's disease. Eur J Neurol. 17 (3): 483-486.

  54. 54.

    Guo WC, Lin GF, Zha YL, Lou KJ, Ma QW, Shen JH: N-Acetyltransferase 2 gene polymorphism in a group of senile dementia patients in Shanghai suburb. ActaPharmacol Sin. 2004, 25 (9): 1112-1117.

    CAS  Google Scholar 

  55. 55.

    Johnson N, Bell P, Jonovska V, Budge M, Sim E: NAT gene polymorphisms and susceptibility to Alzheimer's disease: identification of a novel NAT1 allelic variant. BMC Med Genet. 2004, 5: 6-

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Golab-Janowska M, Honczarenko K, Gawronska-Szklarz B, Potemkowski A: The role of NAT2 gene polymorphism in aetiology of the most frequent neurodegenerative diseases with dementia. Neurologia i neurochirurgiapolska. 2007, 41 (5): 388-394.

    Google Scholar 

  57. 57.

    Hein DW, Doll MA: Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics. 2012, 13 (1): 31-41. 10.2217/pgs.11.122.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Deitz AC, Rothman N, Rebbeck TR, Hayes RB, Chow WH, Zheng W, Hein DW, Garcia-Closas M: Impact of misclassification in genotype-exposure interaction studies: example of N-acetyltransferase 2 (NAT2), smoking, and bladder cancer. Cancer Epidemiol Biomarkers Prev. 2004, 13 (9): 1543-1546.

    CAS  PubMed  Google Scholar 

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We thank the patients and their families as well as those individuals who donated samples to the bio-repository. Thanks to research coordinators Jennifer Lash, Jill Searcy, and Audrey Strongosky from Mayo Clinic Jacksonville for assistance with sample collection and to Mark Doll, Alexandra Soto-Ortolaza and Jennifer Adamson for technical assistance. The Society for Progressive Supranuclear Palsy brain bank is supported by a grant to Dr. Dickson from CurePSP, Inc. This research was supported by the University of Louisville Center for Environmental Genomics and Integrative Biology award number P30ES014443. Dr. Litvan is partially supported by NIH R01 PAS-03-092, National Parkinson Foundation, Parkinson Support Center of Kentuckiana. Dr. Litvan is founder and CEO of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3). Dr. Rai is supported by the Wendell Cherry Chair endowment for clinical trial research and the JG Brown Cancer Center. Dr. Hein was supported by NIH R01-CA034627. Dr. Wszolek is partially supported by the NIH 1RC2-NS070276, P01-NS057567, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030). Dr. Uitti is partially supported by the NIH P01- NS057567, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030). Drs. Dickson, Uitti, Wszolek, Ross and Rademakers are supported by NIH P50-NS072187, NIH P50-NS072187-01S2, and NIH P50-AG16574.

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Correspondence to Irene Litvan.

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Competing interests

The authors declare that they have no competing interests. This research was conducted in accordance with institutional review board approved procedures.

Authors' contributions

LFP participated in study conception and design, carried out NAT genotyping, assisted in data analysis and was primarily responsible for drafting the manuscript. ACC performed statistical analysis and assisted in data interpretation and manuscript preparation. OAR participated in study design and iPLEX genotyping and manuscript critique. RR helped with study design and DNA preparation. DWD, RJU and ZWK provided samples and were involved in manuscript review and critique. SNR assisted in statistical analysis and data interpretation. MJF participated in study design and manuscript critique. DWH participated in study design, data analysis, and manuscript critique. IL was responsible for study conception, design and manuscript review and critique.

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Potts, L.F., Cambon, A.C., Ross, O.A. et al. Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study. BMC Med Genet 13, 16 (2012).

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  • Progressive supranuclear palsy (PSP)
  • N-acetyltransferase 2 (NAT2)
  • Tauopathy
  • Single nucleotide polymorphisms (SNPs)
  • Parkinson's disease (PD)