Study On LRRK2,GBA,SNCA,Parkin Gene Polymorphisms And Their Correlation With Clinical Phenotypes In Patients With Parkinson’s Disease

Background: As the second most common movement disorders,Parkinson’s disease(PD)has dozens of clinical features occurred before or after the loss of dopaminergic neurons,including motor and non-motor symptoms.At present,PD is considered to be caused by a combination of aging,genetic and environmental risk factors.With further researches on genetics in the PD population,it has been found that many genetic mutations are related to familial or sporadic PD.Among them,LRRK2,SNCA,GBA and Parkin genes have been proven to be the common risk factors,and variants of these genes at different sites have been reported.Many studies focused on screening the mutation sites of related genes in the PD population,but researches on the correlation of mutation sites with clinical symptoms were relatively lack.The mechanism of these gene mutations leading to PD is still largely unknown.If researches on the correlation between genetic polymorphism and clinical manifestations could be supplemented,it will helpful to better understand the potential pathogenesis and phenotypic heterogeneity of PD.Objective:This study aimed to explore the single nucleotide polymorphisms(SNPs)of LRRK2 R1628P,LRRK2 G2385R,GBA L444P,SNCA rs356219 and Parkin S/N 167 in sporadic PD patients in this region and their association with the clinical manifestations of PD.And the correlation between the variation of some sites and the risk of PD was investigated.Methods: 165 patients with sporadic PD in Northern Jiangsu People’s Hospital from May 2018 to May 2020 and 94 healthy people of our hospital in the same period were collected as PD group and control group,respectively.The polymorphisms of LRRK2R1628P,LRRK2 G2385 R and GBA L444P in PD patients and healthy people were analyzed by fluorescent PCR,and the polymorphisms of SNCArs356219 and Parkin S/N167 in 165 patients with PD were detected by Sanger DNA sequencing.The motor and non-motor symptoms of PD patients were evaluated with corresponding scales.The carrying status of mutant genes between patients with PD and healthy people were compared,and the relationship between polymorphisms of different gene loci and clinical symptoms in patients with PD was analyzed.Results:1.There was no significant difference in age or sex composition between the PD patients and control group,and the genotypes of each locus were in keeping with the law of Hardy-Weinberg balance(P > 0.05).2.The difference of allele frequency distribution of LRRK2 G2385 R locus between the PD group and the control group was statistically significant(OR=5.257,P=0.003).The carrying rate of mutant gene “A” in the PD group(14.5%)was significantly higher than that in the control group(3.2%).There was no significant difference in allele frequency distribution of LRRK2R1628P or GBA L444 P loci between the two groups.3.The average age and onset age of LRRK2 gene G2385R mutation carriers(GA+AA)in PD patients were significantly lower than those in non-carriers(P = 0.028 and 0.014,respectively).At the same time,there was statistical difference in the sex ratio between carriers and non-carriers(P= 0.025),and the proportion of men among carriers(29%)was significantly lower than that of non-carriers(54%).After Logistic regression,there was significant difference in gender between carriers and non-carriers(OR=0.351,P= 0.032).4.Only 5 cases of GBA gene L444 P mutation gene carriers were detected in 165 PD patients.After analyzing the clinical characteristics of the 5 carriers,no other characteristics were found except for the symptoms of constipation in 5 carriers.5.There were significant differences in PSQI score and FSS score among patients with different genotypes of SNCA gene rs356219 locus(P = 0.013 and 0.001,respectively).After comparison between groups,the FSS score of patients with AA genotype was found to be higher than that of patients with GG and GA genotypes(P<0.001 and P=0.003,respectively).The PSQI score of PD patients with AA genotype was significantly higher than that of GG genotype group(P=0.032 and 0.021,respectively).6.The difference of SCOPA-AUT score in patients with different genotypes of PD at Parkin S/N167 locus was statistically significant(P=0.014),and the SCOPA-AUT score of patients with AA genotype was significantly higher than that of PD patients with GG genotype(P= 0.004).After adjusting and analyzing the influencing factors of SCOPA-AUT score,the Parkin S/N 167 site polymorphism still significantly affects SCOPA-AUT score(P = 0.001).After grouping PD patients according to exercise phenotype,it was found that the mutation rate of mixed PD patients(90.9%)was significantly higher than that of PIGD type(66.7%)and TD type(62%)PD patients(P= 0.001).7.Among the 165 patients,17 cases did not carry the site mutation gene,65 cases carried one of the mutation genes,and 83 patients carried more than two kinds of mutation genes(71 cases carried two kinds of mutations and 12 cases three kinds of mutations).Patients were divided into above three groups,it was found that there were significant differences in NMSQ score and FSS score among the three groups(P=0.043 and 0.019,respectively).Among them,the NMSQ and FSS scores of only one mutation gene carrier and those with more than two mutation genes were significantly higher than those without mutation gene.Conclusion:1.LRRK2G2385R locus polymorphism was thought to be a risk factor for sporadic PD in northern Jiangsu,and its mutation gene “A” increased the risk of PD.Female PD patients might be more prone to LRRK2 G2385R locus mutation.2.Patients with SNCA gene rs356219 locus AA genotype had more severe fatigue symptoms than those with GG and GA genotypes.Carriers of SNCA gene rs356219 locus mutation had a higher risk of sleep disorders than non-carriers.3.Patients with sporadic PD in this region had a higher risk of autonomic nervous function symptoms in patients with Parkin S/N167 site A/A genotype;the mutation gene "A" at this locus might be a risk of mixed PD factor.4.The non-motor symptoms of PD patients carrying the detected locus mutation gene were more than those of non-carriers,and the fatigue symptoms were heavier than non-carriers.However,the types of non-motor symptoms and the severity of fatigue symptoms were not positively correlated with the number of mutant genes.