Correlation Between Parkinson’s Disease Risk Gene Polymorphism And Disease Progression

Background& Objective: Parkinson’s Disease(PD)is a common neurodegenerative disease associated with middle and old age,affecting about 10 million people worldwide.It is a disease caused by age,environment,genetics and other complex causes,which may be related to oxidative stress,mitochondrial dysfunction and inflammation.Its pathological features are nigra selective loss of dopaminergic neurons in the striatum and Lewy bodies formation,resulting in static tremor,muscle rigidity,bradykinesia and motor symptom such as abnormal gait posture,and autonomic nerve function disorder,affective disorders,cognitive dysfunction,sleep disorders,gastrointestinal dysfunction and the movement symptoms.This complex movement disorder is mostly caused by genetic and environmental factors and is the result of complex interactions between genetic susceptibility(SNCA,MAPT or LRRK2 genes),aging and environmental factors(pesticides,smoking,tea,coffee,alcohol and vitamin D).Sporadic PD accounts for about 90%.Mutations only partially explain the aggregation of familial PD,most of which are sporadic PD that has not been explained by single gene mutations.Genetic polymorphism may affect the specific disease characteristics of PD and play an important role in the phenotypic diversity of PD.Previous studies have shown that,alpha-synuclein gene(SNCA)、leucine-rich repeat kinase 2 gene(LRRK2)、bone marrow stromal cell antigen 1 gene(BST1)、 cyclin G-associated kinase gene/diacylglycerol kinase theta gene(GAK /DGKQ)、human leukocyte antigen gene(PARK18/HLA-DRA)、catechol-O-methy-ltransferase gene(COMT)、monoamine oxidase B gene(MAOB)、serine threonine kinase 39 gene(STK39)、microtubule-associated Tau protein gene(MAPT)、brain-derived neurotrophic factor gene(BDNF)、cryptochrome 1/2 gene(CRY1/CRY2)、clock related genes(Tef)have risk correlation with PD.Most studies have analyzed the relationship between single nucleotide polymorphisms of genes and the risk of sporadic PD.As for the gene-gene and gene-environment interaction,whether single nucleotide variations of multiple genes and multiple loci are related to the disease progression of PD patients has been rarely discussed.There is little discussion at present.In this study,23 sites of 14 PD risk genes were selected.SNCA gene(rs11931074,rs356219,rs3857059,rs6532194),LRRK2 gene(rs1994090,rs2046932,rs2708453,rs34778348,rs4768212,rs7304279),BST1 gene(rs11931532,rs4698412),COMT gene(rs4680),CRY1 gene(rs2287161),CRY2 gene(rs10838524),Tef gene(rs738499),DGKQ(rs11248060),GAK gene(rs1564282),MAOB gene(rs1799836),MAPT gene(rs242562),HLA-DRA gene(rs3219882),STK39 gene(rs2390669)and BDNF gene(rs6265)were combined to analyze the correlation between these sites and PD and its progression.To explore the correlation between PD risk gene polymorphism and disease progression in sporadic PD population in China.Methods: A case-control study was conducted to select 173 PD patients and 196 healthy patients admitted to Nanjing brain hospital from March 2014 to October 2017 as subjects.Point of the baseline and follow-up,all patients with PD the UPDRS,H-Y in installment,HAMD,HAMA,PDNMSQ,PDSS,MMSE scale related to evaluation and follow-up of 3 years,calculate the UPDRS Ⅲ difference than the fixed number of year,fixed number of year than MMSE difference,MOCA difference than the fixed number of year,and H-Y in installment transformation.Mass ARRAY?SNP was used to detect 23 loci of 14 genes including SNCA,LRRK2,BST1,COMT,CRY1,CRY2,DGKQ,GAK,MAOB,HLA-DRA,STK39,MAPT,BDNF and Tef.To explore whether SNCA,LRRK2,BST1 and other PD related gene polymorphisms are related to the onset of PD and the progress of motor symptoms and non-motor symptoms.Results: 1.There is a strong linkage unbalance inheritance between three sites of SNCA gene(rs11931074,rs356219 and rs3857059);There is a strong linkage unbalance inheritance between the five LRRK2 loci(rs1994090,rs2046932,rs2708453,rs4768212 and rs7304279).2.Rs11931074 T allele of SNCA gene(OR=1.534,P=0.004),rs34778348 A allele of LRRK2 gene(OR=2.478,P=0.003),rs7304279 T allele of LRRK2 gene(OR=2.852,P <0.001),rs4698412 A allele of BST1 gene(OR=1.378,P=0.033)were correlated with PD risk.The allele of SNCA gene rs6532194 C(OR=0.606,P=0.001)is negatively correlated with the risk of PD,and may have a protective effect on PD.3.The higher the number of variation sites,the higher the risk of PD(OR=6.708,P=0.002).4.As the patient progresses,rigidity,bradykinesia,baseline and follow-up axial symptoms,UPDRS II,UPDRS Ⅲ,UPDRS IV,HAMD,HAMA,PDNMSQ,MOCA,MMSE,H-Y in installment,LED score difference had statistical significance(P< 0.05).5.Binary Logistic regression results indicated that the onset age was late(P= 0.049),the severity of axial symptoms at baseline(P=0.018),and the H-Y stage progression were positively correlated;LRRK2 rs7304279 T allele(P=0.019)was negatively correlated with H-Y stage progression.6.Multivariate linear regression suggested that the late onset age(P=0.033,P=0.009)and SNCA rs1193107 T allele(P=0.008,P=0.046)were positively correlated with the progression of MMSE and MOCA.BST1 rs4698412 A allele(P=0.045)and SNCA rs1193107 T allele(P=0.014)were positively correlated with UPDRS Ⅲ progression.Conclusion: 1.PD patients with obvious tremor show relatively slow progress.2.The older age of onset,the more severe axial symptoms at baseline,SNCA rs11931074 T allele and BST1 rs4698412 A allele are risk factors for the progress of PD patients’ motor symptoms.3.The LRRK2 rs7304279 T allele was negatively correlated with the severity of PD patients.4.In addition,PD patients with late onset age and SNCA rs11931074 T allele are more likely to have gradually aggravated cognition.