A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease

Abstract

Prior studies have established an inverse association between cigarette-smoking and the risk of developing Parkinson's disease (PD), and currently, disease-modifying potential of the nicotine-patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C which encodes a synaptic-vesicle protein in PD-vulnerable substantia-nigra (P=1×10-7 for gene-smoking interaction on PD risk), and CG14691 which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2×10-11 for nicotine-paraquat interaction on gene-expression). SV2C is biologically plausible because nicotine enhances release of dopamine through synaptic vesicles, and PD is caused by depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5×10-10). Taken together, cross-validating evidence from humans and Drosophila suggest SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease

“…SV2 proteins appear to promote vesicular function in various ways, perhaps in part by stabilizing transmitter content in the vesicle through neurotransmitter interaction with the protein's heavily glycosylated intraluminal loop (32,33) or by coordinating vesicular mobilization (24,25,44,45) or by interacting with synaptotagmin-1 to facilitate calciumstimulated exocytosis (26-30, 46, 47). Though only SV2A has been strongly implicated in epilepsy, recent evidence has hinted at a potential link between SV2C, dopamine and PD (37,48,49). Our neurochemical data directly indicate that SV2C plays a particularly important role in the dopaminergic nigrostriatal pathway.…”

“…SV2C is distinguished from SV2A and SV2B by its enriched expression in the basal ganglia and preferential localization to dopaminergic cells in mice (34,35). Intriguingly, SV2C was recently identified as a genetic mediator of one of the most robust environmental modulators of PD risk: nicotine use, which is strongly protective against PD (36,37). Variation within the SV2C gene was also found to predict PD patient sensitivity to L-DOPA (43).…”

Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson's Disease. A Perspective

“…We were interested in identifying the genetic variations that were associated with enhanced or diminished effects of smoking/nicotine and caffeine on PD risk reduction, with the hope that they would be useful as PGx markers for prevention and treatment. We found that the caffeine effect is associated with polymorphisms in GRIN2A, which encodes the NMDA glutamate receptor subunit 2A [40], and that the nicotine effect is associated with polymorphisms in SV2C which encodes the synaptic vesicle protein 2C [41]. The significance of GRIN2A and SV2C in the central nervous system, the etiology of PD, and their intermediary roles in the effects of caffeine and nicotine on neurotransmission have been well-documented [46][47][48][49][50].…”

“…We conducted two genome-wide gene-drug interaction studies for PD; in one [40] the drug was caffeine, in the other [41] the drug was nicotine. Nicotine and caffeine are neuroprotective in animal models [42,43] and are robustly associated with reduced risk of PD in humans in epidemiological studies [44,45].…”

“…Thus it was astounding to identify genes with such strong biological plausibility via hypothesis-free GWAS. In fact, in genome-wide expression studies in a Drosophila model of PD, we identified the SV2C homologue as the single most significant gene in the protective effect of nicotine against paraquat-induced toxicity [41]. Our results suggest (1) GRIN2A genotype is associated with efficacy of caffeine in protecting against PD and (2) SV2C genotype is associated with response to nicotine, where allele dosage correlates with benefit, no response, or possibly harm (the latter was unexpected).…”