The goal of our research is to translate the advances in genetics into clinical applications and develop novel neuroprotective therapies for Parkinson's disease (PD) targeted on appropriate genotypes for optimal safety and efficacy. PD is a progressive movement disorder that affects 1-2% of the population over the age of 60, and many who are younger. The prevalence of PD is expected to double in the next 20 years and continue to rise with the aging of the population. Symptomatic treatment is available, but progression of disease and complications of therapy cause increasing disability. Presently, there is neither a cure nor an effective treatment that can prevent the disease or delay its onset. Clinical neuroprotective trials have not been successful. PD susceptibility is determined by cumulative and interactive effects of genes and environmental factors;therefore, protection against PD may be possible if the right neuroprotective therapy is targeted on the specific genotypes that promote their beneficial effects. Nicotine and caffeine are neuroprotective in animal models and are robustly associated with reduced risk of PD in humans. We propose to identify the genes that enhance or diminish the effects of smoking/nicotine and caffeine. The genes will in turn become targets for drug development, markers for subdividing patients in clinical trials, and a basis for individualized therapy. We have planned a novel integrated approach, using Drosophila for its powerful genetic techniques and NeuroGenetics Research Consortium (NGRC) for its large well-characterized patient population. The human studies in itself will be comprehensive and include hypothesis-neutral genome-wide studies and hypothesis- driven candidate gene and pathway analyses. The following experiments will be performed: (1) a genome- wide gene-environment interaction study, (2) deficiency screening in the paraquat Drosophila model to identify loci that modify rescue by nicotine and caffeine, and testing the human homologues in NGRC cases and controls, (3) testing human candidate genes and regulatory regions in pathways of interest for their effect on smoking- or coffee-associated PD risk reduction, (4) replication in independent studies. Through these complementary studies, we aim to identify and confirm genetic loci that affect risk of PD through interaction with smoking or coffee, to form the basis for development of predictive markers and therapeutic targets.
This study aims to identify genes that interact with environmental compounds that may reduce the risk of developing Parkinson's disease (PD). The new knowledge will enable development of novel personalized therapeutics for PD prevention.
|Houser, Madelyn C; Chang, Jianjun; Factor, Stewart A et al. (2018) Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease. Mov Disord 33:793-804|
|Payami, Haydeh (2017) The emerging science of precision medicine and pharmacogenomics for Parkinson's disease. Mov Disord 32:1139-1146|
|Simon, David K; Wu, Cai; Tilley, Barbara C et al. (2017) Caffeine, creatine, GRIN2A and Parkinson's disease progression. J Neurol Sci 375:355-359|
|Wang, Liyong; Maldonado, Lizmarie; Beecham, Gary W et al. (2016) DNA variants in CACNA1C modify Parkinson disease risk only when vitamin D level is deficient. Neurol Genet 2:e72|
|Hamza, Taye H; Hill-Burns, Erin M; Scott, William K et al. (2014) Glutamate receptor gene GRIN2A, coffee, and Parkinson disease. PLoS Genet 10:e1004774|
|Payami, Haydeh; Factor, Stewart A (2014) Promise of pharmacogenomics for drug discovery, treatment and prevention of Parkinson's disease. A perspective. Neurotherapeutics 11:111-6|
|Hill-Burns, E M; Singh, N; Ganguly, P et al. (2013) A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease. Pharmacogenomics J 13:530-7|
|Hill-Burns, E M; Hamza, T H; Zabetian, C P et al. (2011) An attempt to replicate interaction between coffee and CYP1A2 gene in connection to Parkinson's disease. Eur J Neurol 18:e107-8; author reply e109|
|Hamza, Taye H; Chen, Honglei; Hill-Burns, Erin M et al. (2011) Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet 7:e1002237|
|Hill-Burns, Erin M; Factor, Stewart A; Zabetian, Cyrus P et al. (2011) Evidence for more than one Parkinson's disease-associated variant within the HLA region. PLoS One 6:e27109|