Association Analyses Between Medication Responsiveness And Genetic Polymorphisms On Levodopa Metabolic Pathway In Parkinson’s Disease Patients

Section I Associated Loci Screening on Levodopa Metabolic Pathway with Medication Responsiveness in Parkinson’s Disease PatientsObject:As a progressive neurodegenerative disease,Parkinson’s disease(PD)has brought suffering to patients and great burden to our society.Differentiated responsiveness to medication aggravates the difficulty on treatment.So far,age,disease duration and other factors have been found associated with medication responsiveness by numerous studies.Genetic factors are also indicated.Our study aimed to explore the potential association between medication responsiveness and polymorphisms of genes on levodopa metabolic pathway(DDC,DRD2,DRD5,COMT,and SLC6A3),in order to provide evidence for precise treatment.Methods:We included 55 PD patients.We evaluated the medication responsiveness by levodopa challenge test.Through Next Generation Sequencing,we acquired genetic profile of DDC,DRD2,DRD5,COMT and SLC6A3 in all the patients.Then,we screened for associated polymorphism loci on levodopa metabolic pathway with levodopa responsiveness by Logistic regression analysis.Results:Twenty-six of the 55(47.3%)PD patients we found to be "good responders",and 29 of the 55(52.7%)PD patients we found to be "poor responders".We did not find difference in demographic profile.After data screening and processing,we discovered 14 common SNPs and 0 common Indel.We conducted genotype and allele analysis on those loci and found DRD2 rs1076560 associated with better response to levodopa(genotype:p=0.022,OR=9.19;allele:p=0.004,OR=10.98;Logistic regression).Other loci were not found associated(p>0.05).Conclusions:We discovered the association between DRD2 rs1076560 and levodopa responsiveness in PD patients.Allele A carriers responded better to levodopa and had their motor symptoms more alleviated under levodopa-therapy than non-carriers.Such conclusion needs further validation in our subsequent study.Section Ⅱ Associated Loci Validation on Levodopa Metabolic Pathway with Medication Responsiveness in Parkinson’s Disease PatientsObject:We discovered DRD2 rs1076560 associated with levodopa responsiveness by analyzing the association between the result of levodopa challenge test and genetic data in the first section of this study.In this section,we were to further validate the conclusion in a population of larger scale.Methods:We included 237 PD patients.We acquired genetic profile by Next Generation Sequencing and grouped the 237 PD patients by DRD2 rs1076560 allele.Then,we compare the difference in prescribed dose of dopaminergic medications between the two groups,considering gender,age,disease duration and other factors.Results:We calibrated difference in gender,age,disease duration and other factors according to different rs 1076560 allele carrier.Then,we found statistical difference in prescribed dose of dopaminergic medication between patients of the two rs 1076560 allele groups(levodopa:p=0.014;LED:p=0.039;Mann-Whitney U test).Conclusions:Compared to non-carriers,rs 1076560 A carriers could take lower dose of dopaminergic medications in order to reach the same extent of disease alleviation,indicating better dopaminergic medication response in those patients.