| Objective:Parkinson’s disease is a common nervous systemic disease in old people. The clinical features of PD include resting tremor, bradykinesia, rigidity and postural instability. PD is a chronic disease with a greater cumulative prevalence than one per thousand people[1]. The cardinal pathologic features are the selective loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies. Various medical treatments improve PD symptoms but do little to deter disease progression. The identification of genetic risk factors associated with PD would help to elucidate the pathogenesis of the disease. An abnormal aggregation of the alpha-synuclein protein is believed to be a critical step in the molecular pathogenesis of the disease. The present further supports accumulating evidence that genetic variation of alpha-synuclein plays an important role in the aetiology of PD. The role that SNCA polymorphisms play in the development of PD has been investigated during the past decade with conflicting results. Several studies have previously suggested an association between SNCA polymorphisms and an increased risk of PD. However, some of these studies have failed to confirm such an association. The exact relationship between genetic polymorphisms of SNCA and susceptibility to PD has not been entirely established. To clarify the effect of SNCA on the risk of PD and to estimate the strength of the postulated genetic association, our study involves a meta-analysis of all published case–control observational studies.Methods:1 Identification of relevant studies and eligibility criteria. We established a protocol with pre-defined inclusion criteria and bibliographic search terms. The protocol was applied to all subsequent programs. To identify all articles that examined the association between SNCA polymorphisms and PD, an electronic search of the Pub Med, MEDLINE and PDGene databases was conducted. The keywords used for the literature search were the following: “Parkinson’s disease,’’ ‘‘Parkinsons disease,’’ ‘‘Parkinson disease,’’ ‘‘PD”, “Alpha-synuclein”, “α-synuclein”, “SNCA” in combination with “variant”, “mutation”, “polymorphism,” “genetics” and “SNP” or “single nucleotide polymorphism”. We selected case-control studies published in English and investigated the association between SNCA genotypes and the risk of PD. All selected articles were examined for their appropriateness. The following inclusion criteria had to be fulfilled: 1) case-control study design, 2) clear definitions of cases and controls, 3) data on genotype distributions were available for the patients and the control subjects, 4) data on any/some or all polymorphisms of SNCA, 5) polymorphisms for which at least four studies provided data, 6) genotype distribution of the control genotypes conformed with the Hardy-Weinberg equilibrium. The following criteria were excluded: 1) case reports, 2) family-based design and 3) studies with no risk estimation or no raw data from which risk could be calculated after contacting the authors.2 Data extraction. Two reviewers independently extracted data from published sources. From each study, the following information was extracted: name of the first author, year of publication, country, ethnic origin of the studied population, number of patients and control subjects, genotyping methods and the genotype distributions. Genotype distributions reported in percentages were converted to numerical figures. We did not define any minimum number of patients as a criterion for study inclusion in our meta-analysis. In order to assess the quality of studies a standardized extraction form was used to assign a quality score to each study. Quality scores ranged from 0-20. When the studies included either data from various geographic regions or data from more than one population, we considered each region or population as a separate study. If there were publications overlapping with other studies, the most complete or most recent report was given precedence.3 Statistical analysis. The meta-analysis was performed to examine the overall association for genotypes. To measure the strength of genetic association, the odds ratios(Ors), together with the 95% confidence interval(CI) were calculated. Three genetic models of inheritance were examined as follows: dominant model(AA+AB versus BB), recessive model(AA versus AB+BB) and AA versus BB. Next, subgroup analyses were performed based on ethnicity(Asian and Caucasian). All analyses were performed using the statistical software STATA11.0. Two-sided P values less than 0.05 were considered statistically significant, unless otherwise stated.Results:1 Study characteristics. We identified 19 published articles addressing the relation between SNCA and PD. The Alexis Elbaz publication involved 14 separate case-control studies; therefore, these studies were separately included in the pooling analysis. We included the meta-analysis results for which a minimum of four independent studies provided data; therefore, we included data concerning the following SNPs: rs10005233, rs11931074, rs181489, rs2583988, rs2619363, rs2619364, rs2737029, rs356186, rs356219 and rs894278.2 Summary statistics.(1) Sixteen studies on the rs181489 polymorphism were considered for which all the data concerned Caucasian populations. The odds ratios for Caucasians in the dominant model, recessive model and TT versus CC were 1.273(1.133, 1.429), 1.572(1.373, 1.801) and 1.678(1.455, 1.934), respectively.(2) Six studies on the rs356186 polymorphism were considered, for which all the data concerned Caucasian populations. The odds ratios for Caucasians in the dominant model, recessive model and AA versus GG were 0.747(0.658, 0.848), 0.715(0.513, 0.997) and 0.653(0.466, 0.913), respectively.(3) Eighteen studies on the rs356219 polymorphism were considered for which all the data concerned Caucasian populations. The odds ratios for Caucasians in the dominant model, recessive model and GG versus AA were 1.255(1.136, 1.385), 1.381(1.192, 1.600) and 1.523(1.282, 1.808), respectively.(4) Six studies on the rs894278 polymorphism were considered, of which all the data concerned Asian populations. The odds ratios for Asians in the dominant model, recessive model and GG versus TT were 1.272(1.174, 1.377), 1.341(1.208, 1.488) and 1.493(1.331, 1.675), respectively.(5) Eighteen studies on the rs2583988 polymorphism were considered, of which all the data concerned Caucasian populations. The odds ratios for Caucasians in the dominant model, recessive model and TT versus CC were 1.275(1.186, 1.371), 1.289(1.133, 1.466) and 1.409(1.233, 1.609), respectively.(6) Six studies on the rs2619364 polymorphism were considered, of which all the data concerned Caucasian populations. The odds ratios for Caucasians in the dominant model, recessive model and GG versus AA were 1.136(0.999, 1.292), 1.303(1.042, 1.630) and 1.346(1.068, 1.696), respectively.(7) Four studies on the rs10005233 polymorphism with data from three Caucasians and one Asian population were considered. The overall estimated odds ratios in the dominant model, recessive model and CC versus TT were 1.359(1.134, 1.630), 0.862(0.707, 1.052) and 0.855(0.675, 1.084), respectively.(8) Twenty studies on the rs11931074 polymorphism, with data from fifteen Caucasian populations and five Asian populations, were considered. The overall estimated odds ratios in the dominant model, recessive model and TT versus GG for all studies combined were 1.419(1.300, 1.548), 1.487(1.361, 1.626) and 1.798(1.572, 2.057), respectively.(9) Seven studies on the rs2619363 polymorphism, with data from six Caucasian populations and one Asian population, were considered. The overall estimated odds ratios in the dominant model, recessive model and TT versus GG were 1.088(0.935, 1.266), 1.216(0.938, 1.576) and 1.250(0.956, 1.634), respectively.(10) Six studies on the rs2737029 polymorphism, with data from five Caucasian populations and one Asian population, were considered. The overall estimated odds ratios in the dominant model, recessive model and GG versus AA were 1.193(0.878, 1.622), 1.274(0.974, 1.665) and 1.355(0.898, 2.044), respectively.ConclusionThis meta-analysis showed that eight out of these 10 candidate SNPs may be associated with PD risk. Significant association was found between PD and the following SNPs: rs181489, rs356186, rs356219, rs894278 rs2583988, rs2619364, rs10005233 and rs11931074. Among these SNPs, rs356186 was found to be the only SNP that may play a protective role in Parkinson’s disease. These results suggest that the SNCA gene may be associated with PD. Conclusion:... |
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