Department of Genetics, University of Delhi South Campus, All India Institute of Medical Sciences, New Delhi, India.
Pharmacogenet Genomics. 2011 Dec;21(12):790-7. doi: 10.1097/FPC.0b013e32834bcd74.
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.
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.
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.
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.
已知杀虫剂/神经毒素/自由基诱导的氧化应激导致多巴胺能神经元易感性，从而促进散发性帕金森病（PD）。本研究调查了药物代谢酶（DME）和氧化应激途径中的基因多态性对北印度队列中 PD 易感性和严重程度的贡献。
招募了 339 名符合英国 PD 脑库标准的 PD 患者和 344 名年龄、性别和种族匹配的对照者。进行单变量和多变量分析以检验等位基因、基因型和单倍型关联，并评估 13 个基因的 18 个多态性的基因-基因相互作用。根据 Hoehn 和 Yahr（HY）量表和统一帕金森病评定量表 III 评分计算疾病严重程度，并比较标记物基因型类别的差异。
在单变量和多变量分析中，GSTO1-rs4925（P=0.04）和 NQO1-rs1800566（P=0.02）与疾病易感性相关。PON2-rs7493（P=0.00009 与 UPDRS III，P=0.003 与 HY）与疾病严重程度的显著和新颖关联在经过 Bonferroni 校正后仍然保留。将队列分为早发性 PD（YOPD，n=90 例，104 例对照）和晚发性 PD（n=249 例，240 例对照）后，观察到 DME 中几个单核苷酸多态性（SNP）与 YOPD 相关。
NQO1、PON2 和 DME 基因（本研究）以及 NAT2（先前的研究）与印度人中的 PD 相关可能表明存在固有特定人群的遗传易感性。这可能与过去几十年中我国环境毒素的增加和杀虫剂的滥用有关，这可能表明存在基因-环境相互作用，这可以解释印度人中 YOPD 发病率的增加。
