Leads from xenobiotic metabolism genes for Parkinson's disease among north Indians.
OBJECTIVE
Pesticide/neurotoxin/free radical-induced oxidative stress leading to dopaminergic neuronal vulnerability is known to promote sporadic Parkinson's disease (PD). This study investigated the contribution of polymorphisms in genes from drug-metabolizing enzymes (DMEs) and the oxidative stress pathway to PD susceptibility and severity among a north Indian cohort.


METHODS
Three hundred and thirty-nine PD patients diagnosed using UK PD brain bank criteria and 344 age-, sex-, and ethnicity-matched controls were recruited. Univariate and multivariate analyses were carried out to test allelic, genotypic, and haplotypic associations, and gene-gene interactions were assessed for 18 polymorphisms from 13 genes. Disease severity was calculated on the basis of the Hoehn and Yahr (HY) scale and Unified Parkinson's Disease Rating Scale III scores and was compared among the genotypic categories of markers.


RESULTS
An association of GSTO1-rs4925 (P=0.04) and NQO1-rs1800566 (P=0.02) in univariate and multivariate analysis (P=0.01 and P=0.03, respectively) with disease susceptibility was observed. Significant and novel association of PON2-rs7493 (P=0.00009 with UPDRS III, P=0.003 with HY) with disease severity was retained after Bonferroni correction. On categorizing the cohort into young-onset PD (YOPD, n=90 cases, 104 controls) and late-onset PD ( n=249 cases, 240 controls), the association of several single nucleotide polymorphisms (SNPs) in DMEs was observed with YOPD.


CONCLUSIONS
The association of NQO1, PON2, and DME genes (this study) and NAT2 (previous study) with PD among Indians may point toward an inherent population-specific genetic predisposition. This, probably compounded by an increase in environmental toxins and the indiscriminate use of pesticides in our country in the last few decades, may suggest likely gene-environment interactions, which may explain the increasing incidence of YOPD among Indians.
Department of Genetics, University of Delhi South Campus, All India Institute of Medical Sciences, New Delhi, India.
Sohan
S
Punia
Mitashree
M
Das
Madhuri
M
Behari
Maninder
M
Dihana
Shyla T
ST
Govindappa
Uday B
UB
Muthane
B K
BK
Thelma
Ramesh C
RC
Juyal
D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human