Research On Polymorphisms Of LRRK2 Gene In Patients With Parkinson's Disease

Background and purposeParkinson's disease (PD) is a common neurodegenerative disorder.Hereditary is important cause of this disease. LRRK2 gene is one of the predisposing genes of PD, which is located on chromosome 12q12, encompasses 144 kb,with an ORF consisting of 7581 bp (in 51 exons) and its encoded protein is unusually large (2527 amino acids) set GTP LRRK2 protein and protein kinase enzyme domains in one belongs to the Roco family of highly conserved, and GTP with the protein kinase activity. GTP LRRK2 protein can serve as a scaffold protein for the multi-protein signaling complex to provide a platform together. The variation of this gene is specially involved in some races, such as the G2385R and R1628P polymorphisms were only exist in the population of PD in East Asia. It was reported that G2385R and R1628P polymorphisms could increase the attack rate of PD, but some studies showed that two polymorphisms wasn't associated with PD, As different studies have different results, it has great sense to verificat the different races and in different regions. To explore the LRRK2 gene polymorphism in pathogenesis of PD, We studied the relationship between the LRRK2 gene polymorphisms (G2385R and R1628P) and PD of Han Chinese in Fujian Province,then analyed all the studies on relationship between the LRRK2 gene polymorphisms (G2385R and R1628P) by Meta-analysis.Methods1. The clinical data and extracted the DNA from peripheral blood of 259 cases of PD patients and 257 healthy controls were collected.2. Polymerase Chain Reaction combined with restriction fragment length polymorphism (PCR-RFLP) was used to detected the two variations (G2385R and R1628P) LRRK2 gene of PD patients; for the variation of line carriers and some non-carriers was verified by the sequencing. Then the sex, age, clinical symptoms, UPDRS score and Hoehn-Yahr grade were comparied in different Genotype of PD patients.3. As case-control mode, the distribution of genotype frequencies in 259 cases of PD patients and 257 healthy controls were compared, then the population attributable risk percent (PAR%) of G2385R and R1628P variations was Count and the synergy with gender and age interaction was analysis at the same time.4.Meta-analysis was applicatid to sub-group analysis the G2385R and R1628P Polymorphism of all case-control study. The heterogeneity was assessmentde by Q test, take appropriate statistical model of effect size (OR) combined, and apply different statistical models and sensitivity analysis of the combined effect of test values.Result1, In the detection of G2385R,25 PD patients were GA genotype (9.7%), significantly higher than that of the six cases of GA genotype (2.0%) (x2= 15.57, P <0.0001, OR= 5.243,95% CI= 2.115-12.9). the PAR% of approximately 7.86% was gained. No PD patient with AA genotyp was found. Stratified the age:200 patients with late-onset PD patients,20 cases of GA genotype (10.0%), corresponding to the age of the control group,5 cases of 229 GA genotype (2.2%), both statistically significant difference (x2= 11.886, P= 0.002, OR= 4.978,95% CI= 1.832-13.523), but early-onset PD patients with the corresponding age group no significant difference (x2= 3.691, P= 0.091, OR= 6.538,95% CI= 0.741-57.678).2, In the detection of R1628P detection,,16 were GC genotype (6.2%) in 257 cases of PD patients and 10 cases of GC genotype (3.4%) 298 controls, no significant difference between the two groups (x2= 2.545, P= 0.111). Early-onset and late-onset PD patients with the corresponding age group showed no significant difference.3, The aspects of clinical phenotype (such as sex, age, clinical symptoms, UPDRS score and Hoehn-Yahr grade) of patients carrying G2385R or R1628P were not statistically different.4.As the result of Meta-analysis, the summary odds ratio for studies with polymorphisms of G2385R and R1628P loci of the LRRK2 gene among the East-Asia population were 2.65(95%CI:2.11-3.29, P<0.001),2.08(95%CI:1.60-2.69, P<0.001),respectively when compared with their corresponding common homozygotes. Publication bias was not found in studies with the two loci by Egger linear regression method.Conclusion1, The G2385R variant in the LRRK2 gene may be a risk factor of the late-onset Parkinson's disease in Fujian Han in China.2, The R1628P variant didn't related with the incidence of sporadic Parkinson's disease in Fujian Han population in China.2, In theLRRK2 gene, the G2385R may result in more incidence of Parkinson's disease in East Asia. The R1628P variant was related to the incidence of Parkinson's in China. However, there is difference in different regions.