Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles, CA, USA.
Environ Int. 2013 Jun;56:42-7. doi: 10.1016/j.envint.2013.03.004. Epub 2013 Apr 16.
We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants.
From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1L55M and PON1Q192R) and the promoter region variant (PON1C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California.
The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1Q192R genotypes, but no differences across PON1C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1192QQ and PON155MM (OR range, 2.84-3.57).
Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1L55M or PON1Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures.
我们之前的研究表明，居住环境中接触到有机磷（OP）农药的对氧磷酶（PON1）“慢代谢型”MM 基因型携带者发生帕金森病（PD）的风险增加。在这里，我们用更大的样本量扩展了之前的研究，考虑了其他环境暴露源，并研究了另外两个功能性 PON1 变体。
我们于 2001 年至 2011 年期间招募了加利福尼亚州中部的特发性 PD 病例和社区对照者。我们对三个已知的功能性 PON1 单核苷酸多态性（SNP）进行了基因分型：两个外显子多态性（PON1L55M 和 PON1Q192R）和启动子区域变异（PON1C-108T）。利用基于验证的地理信息系统模型，结合加利福尼亚州农业农药应用记录，评估了居住和工作地址处的二嗪农、氯吡硫磷和对硫磷的环境暴露情况。
居住或工作环境中接触 OP 的白种人，PON1 基因型不同，其比值比（OR）也不同；对于“快代谢型”基因型 ML 或 LL 的暴露携带者，我们估计其比值比（范围，1.20-1.39）低于“慢代谢型”基因型 MM 的暴露携带者（范围，1.78-2.45），而对于“快代谢型”基因型的未暴露携带者而言。我们观察到在 PON1Q192R 基因型中，接触 OP 会导致相似的 OR 增加，但在 PON1C-108T 基因型中没有差异。估计暴露于两者的 OR 最大的是 PON1192QQ 和 PON155MM 的携带型（OR 范围，2.84-3.57）。
几种功能性 PON1 变体可能共同作用，改变环境 OP 暴露对 PD 的风险。虽然 PON1L55M 或 PON1Q192R 单独存在可能足以识别易感性增加，但慢代谢型变体的携带者似乎对 OP 暴露最敏感。
