Polychlorinated Biphenyls (PCBs) and Parkinson's Disease (PD): Effect Modification by Membrane Transporter Variants (S32.004)

Objective: Determine associations of PD with PCBs and investigate modification by variants in the xenobiotic-efflux membrane transporter p-glycoprotein gene ( ABCB1 , p-gp, MDR1 ) Background: PCBs have been inconsistently associated with PD risk. We recently reported significantly increased risk associated with higher serum PCBs in an Alaska Native population and much stronger associations in persons with ABCB1 variants. Here we investigate those associations in another population. Methods: We recruited people with PD (PwPD) and matched controls from the Agricultural Health Study cohort of pesticide applicators and their spouses. PD was confirmed by expert consensus. We genotyped ABCB1 single nucleotide polymorphisms (SNPs) using an Illumina custom array, and measured 15 PCB-congeners in serum using GC-MS. We adjusted for total lipid and used β-substitution to impute undetectable values, and also analyzed summed levels of PCB-118, 138, 153 and 180 (PCB_sum). We assessed associations with PD using logistic regression adjusting for age, gender and state, and examined multiplicative interactions of PCBs and SNPs. Results: Analyses included 97 PwPD and 113 controls. All PCBs were higher in PwPD. For PCB_Sum, compared with the lowest quartile (Q1), odds ratios for Q2, Q3 and Q4 were 1.7, 2.5 and 2.7, respectively (p-trend 0.02). ABCB1 coding variant rs9282564 modified PD-PCB associations: relative to those with below-median PCB_sum, above-median PCB_sum was associated with 1.4-fold (95[percnt]CI 0.7-2.8) greater risk in those with AA genotype, but 11.4-fold (95[percnt]CI 2.8-45) greater risk in those with AG or GG genotype (p-interaction 0.008). Conclusions: In this primarily Caucasian population, as in the Alaska Native population, PCB levels were higher in PwPD than controls. Risk was markedly increased in persons with both above median PCB levels and variants in ABCB1 , suggesting a gene-environment interaction. Study Supported by: NIEHS-R01-ES10803, NIH Intramural Research Program (NIEHS-Z01-ES044007, Z01-ES049030; NCI-Z01-CP010119), Michael J. Fox Foundation, James and Sharron Clark. Disclosure: Dr. Goldman has nothing to disclose. Dr. Kamel has nothing to disclose. Dr. Meng has nothing to disclose. Dr. Korell has nothing to disclose. Dr. Comyns has nothing to disclose. Dr. Umbach has nothing to disclose. Dr. Hoppin has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Marras has nothing to disclose. Dr. Kasten has nothing to disclose. Dr. Chade has nothing to disclose. Dr. Blair has nothing to disclose. Dr. Tanner has received personal compensation for activities with Neurocrine and Ultragenyx Pharmaceuticals as a consultant.