| Objective: Alzheimer’s disease(AD)is the most serious degenerative disease occurring in the central nervous system(CNS),characterized by progressive cognitive impairment and abnormal mental behavior.AD has placed a serious physical,emotional and economic burden for the people all over the world.Age and genetic factors are two major risk factors for Alzheimer’s disease(AD).Genetic factors play important roles in the pathogenesis of AD,and they might be new targets for the treatment of AD.Late-onset Alzheimer’s disease(LOAD)is the most common form of AD,and its pathogenic genes remain unclear.The apolipoprotein E(Apolipoprotein E,APOE ε4)gene,located on chromosome 19,is the only recognized pathogenicity-related gene of LOAD.The large-scale genome-wide association study(GWAS)found that the growth factor receptor-bound protein-associated binding protein 2(GAB2)gene polymorphisms could participate in the susceptibility to AD,however,mechanisms of how GAB2 gene influence the pathogenesis of AD remain still unclear.We conducted this study to identify the association of GAB2 gene polymorphisms with the biomarkers of cerebrospinal fluid(CSF),and to explore the mechanism of GAB2 gene involvement in AD susceptibility.Methods: GWAS is a new strategy to analyze the association of gene variants and complex traits in whole genome range.It can find out all the gene mutations related to some disease.According to the results of GWAS and meta-analysis,we screened four GAB2 gene loci including rs1385600,rs1007837,rs10793294 and rs2373115 as the target gene polymorphic loci.All included gene loci must satisfy with the following standards: 1)minimum call rates=0.9;2)minimum minor allele frequencies(MAF)>0.01;3)Hardy-Weinberg equilibrium test P>0.001.The most important pathological characteristics of AD are the formation of senile plaques and neurofibrillary tangles,which are separately composed of extracellular abnormal aggregation of βamyloid protein(Aβ)and abnormal phosphorylation of tau protein in cells.So,we chose Aβ,total tau(T-tau)and phosphorylated tau(P-tau)as the CSF biomarkers of AD.With the help of the Alzheimer’s disease neuroimaging database(ADNI),we included 627 subjects in our research,containing 206 cognitive normal objects(CN),377 objects with mild cognitive impairment(MCI)and 44 patients with AD.PLINK software was used to get all information of every subjects from the ADNI database,such as the basic characteristics,the GAB2 genotypes and CSF biomarkers.We performed one-way analysis of variance(ANOVA)to examine the differences among continuous variables such as age,time for education,scores of cognitive scale.Chi-square test was developed to analyze categorical variables,including gender and APOE ε4status.A multiple linear regression model was established to analyze the correlation between the selected GAB2 gene loci and the β amyloid protein(Aβ),total tau(T-tau)and phosphorylated(P-tau)in CSF.All results were corrected by Bonferroni method.This method is applicable to the comparison of continuous variables in multiple linear regression model,and can reduce the false positive rate(FDR).The relation of gene locus and CSF protein showed statistical association only when corrected P value(Pc)was less than 0.05,it turn to significant association when Pc was less than 0.01.The statistical analysis included the following two parts: 1)the correlation between GAB2 gene loci and Aβ,T-tau and P-tau of CSF among all the subjects;2)the correlation between GAB2 gene loci and A,T-tau and P-tau in CSF in subgroups(CN group,MCI group,AD group).R 3.12 and PLINK 1.07 software were used to conduct these statistical analyses.Results: In the analysis among all subjects,all gene loci except rs10793294 were related to the level Aβand tau in CSF.Rs1385600 and rs1007837 showed significant association with Aβ,T-tau and P-tau(rs1385600:Aβ β=9.53 Pc=0.0112,T-tau β=﹣7.74 Pc=0.0356,P-tau β= ﹣ 4.47 Pc=0.0116;rs1007837 : Aβ β=10.03 Pc=0.0058,T-tau β= ﹣ 7.89 Pc=0.0278,P-tau β=﹣4.10 Pc=0.0231).Rs2373115 were significantly associated with Aβ and P-tau(Aβ β=8.37 Pc=0.0398,P-tau β=﹣4.04 Pc=0.0329).In subgroup analysis,the GAB2 gene locus was only associated with the level of CSF biomarkers in the subjects of CN group.Rs1385600 and rs1007837 were correlated with the level of T-tau and P-tau in CSF of cognitively normal people,and they were significantly correlated with P-tau(rs1385600:T-tau β=﹣10.04 Pc=0.0398,P-tau β=﹣5.78 Pc=0.0049;rs1007837:T-tau β=﹣10.59 Pc=0.0172,P-tau β=﹣5.80 Pc=0.0027).We found that,compared with other genotypes of rs1385600 and rs1007837,subjects with genotype C/C have the least amount of tau protein in CSF.This prompts that there is dose-dependent relationship between the minimum minor allele C of rs1385600,rs1007837 and the decrease of tau protein(especially P-tau).Both of rs1385600 and rs1007837 showed no association with CSF Aβ in cognitively normal persons.There was no association between rs2373115,rs10793294 and Aβ,T-tau,P-tau levels in the cerebrospinal fluid in the subjects of this group(Pc > 0.05).In MCI group and AD group,there was no correlation between four gene loci and the level of Aβ,T-tau and P-tau in cerebrospinal fluid(Pc > 0.05).Conclusion: GAB2 gene loci rs1385600 and rs1007837 are significantly associated with the level of tau protein especially P-tau in the CSF of cognitively normal people.And the higher the homozygosity of the minimum allele C is,the lower the content of tau protein in cerebrospinal fluid will be.According to the results above,we reasonably deduce rs1385600 and rs1007837 sites are protective sites of Alzheimer’s disease,which may decrease the production of phosphorylated tau protein by participating in the phosphorylation process of tau protein. |
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