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.

Parkin mutations in familial and sporadic Parkinson's disease among Indians.

We observed a mutation frequency of 8.5% in Parkin gene among Indian PD patients based on sequencing and gene dosage analysis of its exons. We identified nine point mutations of which seven are novel and hitherto unreported. These mutations accounted for 14.3% familial PD, 6.9% young onset and 5.9% late onset sporadic PD. Of the 20 PD patients with mutations only two had homozygous mutations and one was a compound heterozygote. Homozygous exonic deletions were absent but heterozygous exon rearrangements were observed in 9.2% of patients (19% familial PD and 4.5% young onset sporadic PD).

Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians.

OBJECTIVES: To investigate the association of (i) seven SNPs and SNP haplotypes in the phase II conjugating enzyme N-acetyl transferase 2 gene; and (ii) slow acetylator phenotype, with the development of young onset (YO) and late onset (LO) Parkinson's disease (PD) among Indians. METHODS: A total of 267 cases (132 YOPD, age at onset < or =40 years; 135 LOPD, age at onset >40 years) and 324 age and sex matched controls (132 for YOPD and 192 for LOPD) were genotyped for NAT2 SNPs. Allelic, genotypic and haplotypic association was tested by chi2 using a case-control approach. Chi2 test of association of acetylation phenotype (by genotype) with PD was also carried out. RESULTS: Of the seven SNPs genotyped, SNP191 was monomorphic and therefore, not included for analysis. With SNPs 590 and 857 a significant allelic [OR (95% CI) 4.147 (2.28-7.54) for A allele and 2.565 (1.34-4.92) for A allele, respectively] and genotypic [OR (95% CI) 0.27 (0.14-0.52) for GG and 0.35 (0.174-0.712) for GG, respectively] association with YOPD was observed. There was a significant allelic and genotypic association of SNP 282 with LOPD [chi2 = 8.92, P = 0.003 and chi2 = 10.2, P = 0.006, respectively]. There was also a significant association of protective and predisposing haplotypes TCGG and TCAG [OR (95% CI) 0.446 (0.31-0.63) and 3.742 (2.0-6.99), respectively] with YOPD and predisposing haplotype TCGA [OR (95% CI) 3.214 (1.43-7.22)] with LOPD. Slow acetylator phenotype was significantly associated with YOPD [OR (95% CI) 2.32 (1.2-4.48)]. CONCLUSION: Specific SNPs and SNP haplotypes in NAT2 and slow acetylator phenotype are significantly associated with YOPD and to a lesser extent with LOPD among Indians.