Session Information
Date: Monday, June 20, 2016
Session Title: Epidemiology and Quality of Life
Session Time: 12:30pm-2:00pm
Objective: Determine whether variants in the xenobiotic efflux membrane transporter p-glycoprotein gene (ABCB1, p-gp, MDR1) modify the association of rotenone and PD.
Background: Use of the insecticide rotenone has been associated with increased risk of PD (Tanner et al, 2011). A recent report identified rotenone as a substrate of the p-glycoprotein membrane efflux transporter (Lacher et al, 2015). We hypothesized that common ABCB1 variants might modify the association of rotenone and PD.
Methods: We recruited people with PD (PwPD) and age-, gender- and state-matched controls from the Agricultural Health Study, a cohort of pesticide applicators and their spouses. PD was confirmed by expert consensus. We genotyped single nucleotide polymorphisms (SNPs) in ABCB1 using an Illumina custom array. Prior use of rotenone was determined by questionnaire. For each SNP, we calculated odds ratios (ORs) and 95% confidence intervals (CI) associated with rotenone use using logistic regression adjusting for matching factors and smoking. We assessed multiplicative effect-measure modification by including a genotype x rotenone product term.
Results: Genotype and exposure data were available for 93 PwPD and 346 controls. We analyzed 10 ABCB1 SNPs with minor allele frequencies >10% and call rates >95%. 50 subjects endorsed prior use of rotenone. As previously reported, rotenone use was associated with increased risk of PD (OR 2.7, 95%CI 1.4-5.1). Several ABCB1 variants modified this association (Table). Rotenone use was associated with a 5.9-fold increased risk in those with rs1989830 CC genotype, but a non-significant 1.9-fold increased risk in those with CT or TT genotype (p-interaction 0.07). Other SNPs similarly modified the association of PD and rotenone, including rs1202172, rs1128503, rs9282564 and rs998671. Differences were particularly evident among men.
| SNP | Genotype | All | Men |
| rs1989830 | CC | 5.9 (2.0-18.1) | 7.4 (1.9-28.7) |
| CT or TT | 1.9 (0.8-4.3) | 2.4 (0.9-6.4) | |
| rs1202172 | TT | 5.7 (1.9-17.5) | 7.2 (1.8-27.9) |
| GT or GG | 1.9 (0.8-4.4) | 2.4 (0.9-6.5) | |
| rs1128503 | CC | 3.5 (1.4-9.8) | 6.9 (1.9-25.3) |
| CT or TT | 2.1 (0.9-5.0) | 2.1 (0.8-5.6) | |
| rs9282564 | AA | 3.0 (1.5-5.8) | 4.0 (1.8-8.8) |
| AG or GG | 1.1 (0.1-14.8) | 1.2 (0.1-21.5) | |
| rs998671 | GG | 3.6 (1.7-7.5) | 5.2 (2.1-12.5) |
| AG or AA | 1.2 (0.3-5.2) | 1.4 (0.3-6.6) |
Conclusions: The association between rotenone and PD differed among variants in the ABCB1 efflux-transporter gene, suggesting a gene-environment interaction. Although statistical power is modest, this finding is consistent with the observation that rotenone may be a p-glycoprotein substrate, and adds to mounting evidence of genetically determined xenobiotic susceptibility in PD etiology.
To cite this abstract in AMA style:
S.M. Goldman, F. Kamel, C. Meng, M. Korell, D.M. Umbach, J. Hoppin, G.W. Ross, C. Marras, M. Kasten, A. Chade, K. Comyns, D. Sandler, A. Blair, C.M. Tanner. Rotenone and Parkinson’s disease (PD): Effect modification by membrane transporter variants [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/rotenone-and-parkinsons-disease-pd-effect-modification-by-membrane-transporter-variants/. Accessed November 22, 2024.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/rotenone-and-parkinsons-disease-pd-effect-modification-by-membrane-transporter-variants/