Email updates

Keep up to date with the latest news and content from BMC Medical Genetics and BioMed Central.

Open Access Highly Accessed Research article

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

Lisa F Potts1, Alex C Cambon2, Owen A Ross3, Rosa Rademakers3, Dennis W Dickson3, Ryan J Uitti4, Zbigniew K Wszolek4, Shesh N Rai25, Matthew J Farrer36, David W Hein57 and Irene Litvan189*

Author Affiliations

1 Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA

2 Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA

3 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA

4 Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA

5 J.G. Brown Cancer Center, University of Louisville, Louisville, KY, USA

6 Department of Medical Genetics, Centre of Applied Neurogenetics, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

7 Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

8 Department of Neurology, University of Louisville, Louisville, KY, USA

9 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

For all author emails, please log on.

BMC Medical Genetics 2012, 13:16  doi:10.1186/1471-2350-13-16

Published: 17 March 2012

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

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