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

Abstract

BackgroundThere 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.MethodsDNA 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.ResultsThe 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).ConclusionsOur 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.

K-variant BCHE and pesticide exposure: Gene-environment interactions in a case–control study of Parkinson’s disease in Egypt

“…Blood-cell-derived genomic DNA (80–100 ng/µL) was genotyped with the EP1 platform on 96.96 Dynamic Array and read by Fluidigm EP1 Genetic Analysis Scanner (Fluidigm Corporation, San Francisco, CA). Twenty-four Candidate SNPs were chosen in genes related to pesticide detoxification [ CYP1B1 (rs1056836) 36 , CYP2B6 (rs3745274) 37 , CYP2C9 (rs1799853, rs1057910) 32 , CYP2C18 (rs2296680) 38 , CYP2E1 (rs2070676) 39 , PON1 (rs662, rs854560, rs854572) 40 , GSTO1 (rs11191972, rs4925) 41 , GSTO2 (rs2297235, rs156697) 41 , NAT1 (rs5030839, rs4987076) 42 , 43 , NAT2 (rs15561) 43 , NQO1 (rs1800566) 9 , COMT (rs4680) 36 , BCHE (rs1803274, rs1799807, rs1126680) 24 , 29 , 44 , PLA2G6 (CM1211192) 45 ] and pesticide transport [ SLC6A3 (rs27072, rs2550956) 14 , 46 ]. Assays include tagged, allele-specific PCR forward-primers and a common reverse primer.…”

Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

“…Candidate gene approaches have implicated a role of VEGF , NAT2 and Park2 in the pathogenesis of PSP. However, none of these loci were associated with disease in a large GWAS, suggesting that these associations either escaped detection due to small effect size or the initial results were spurious in nature [ 152 , 159 , 160 , 161 ]. A risk locus on 11p12-11, containing the genes DDB2 and ACP2 , has been suggested in a pooled GWAS including only 288 pathologically confirmed cases and 344 matched controls, but this locus was not detected in a larger GWAS [ 152 , 162 ].…”