Meta-analysis Of The Association Between Cd33 And Alzheimer’s Disease

Background:Alzheimer’s disease(AD)is a complicated neurodegenerative disease with progressive cognitive impairment common in elderly people.In 2006,the prevalence of AD was 26.6 million around the world,and the number of AD will quadruple by 2050.AD consists of early-onset AD(EOAD)and late-onset AD(LOAD).LOAD,which accounts for the majority of AD,is the result of interaction between environmental and genetic factors.Genetic factors play an important role in it,and the heritability is estimated to be up to 80%.Up to now,the apolipoprotein E(APOE)gene is the only one gene that was certainly recognized to increase the risk of LOAD,but the APOEε4 gene can only interpret 27.3%about the risk of AD onset.Therefore,further efforts are needed to look for risk genes other than APOE.The cluster of differentiation 33(CD33)gene is an immune function protein located in 19p13.33 with several functions,such as cell adhesion,anti-inflammatory signaling,and endocytosis functions.In addition,it is one of the members of the sialic acid-binding Ig-like lectin(SIGLEC)family.Several studies have investigated the important role of CD33 rs3865444 polymorphism in AD.As for rs3865444,the risk allele(C)was related with the overexpression of CD33 on mononuclear cell surface,which is involved in the pathogenesis of AD through downregulation ofβ-amyloid(Aβ)internalization,accumulation of neuritic amyloid pathology,and regulation of microglia levels.Both lines of evidence indicate that CD33 gene could play an important role in susceptibility to AD.In2011,three large-scale genome-wide association studies(GWAS)conducted by Hollingworth et al.,Carrasquillo et al.,and Naj et al.confirmed that the gene CD33 showed signifcantly correlation with LOAD in Europe.After that,the associations between AD and the variants of CD33 have become the focus of many studies.But the conclusions of these studies differ from each other.But the conclusions of these studies are inconsistent.To better illuminate the associations between CD33 and the susceptibility to AD,a meta-analysis was conducted by analyzing and summarizing the relevant studies.Methods:We searched literature in PubMed,EMbase,and Cochrane library up to 1 October2017.Medical Subject Heading(MESH)terms were used:(CD33)AND(((Alzheimer’s)OR dementia)OR Alzheimer disease).Additional studies were screened manually in each qualifying study.The following data were extracted in qualified articles:(I)name of the frst author,(II)publication year,(III)country and ethnicity of origin,(IV)numbers of cases and controls,(V)allele frequency distributions and numbers of different genotypes,(VI)the OR with 95%CI of CD33.Newcastle-Ottawa quality scale(NOS)was selected to evaluate the quality of eligible studies:(I)the selection;(II)the comparability;(III)the exposure.Studies with a score larger than seven points were considered to be of high quality.The following data were extracted:(I)name of the frst author,(II)publication year,(III)country and ethnicity of origin,(IV)numbers of cases and controls,(V)allele frequency distributions and numbers of different genotypes,(VI)the OR with 95%CI of CD33.Stata 11.0 software version 11.0 and R software were selected for statistical analysis.HardyWeinberg equilibrium(HWE)was used to verify the representation of the selected studies.Statistical heterogeneity could be evaluated by Cochran’s Q statistic and I~2 Statistic test.When significant heterogeneity(PQ>0.10 and I~2>50%)was observed,the random-effects model was carry out;in addition,the fxed-effects model was adopted.Taking into account racial differences may affect the relationship between CD33 gene and AD,we conducted a subgroup analyses on the basis of ethnicity(Asian,Caucasian and Negroid).In order to assess the stability of the results,we conducted sensitivity analysis by omitting a single study each time.Funnel plots were generated by the R software to evaluate the potential publication bias.And publication bias was also checked by Egger’s linear regression analysis and Begg’s rank correlation test.Results:In the present meta-analysis,a systematic overview of relevant studies to evaluate the risk between gene CD33 and the susceptibility to AD have been accomplished.Eighty-fve articles were searched from PubMed,EMbase,Cochrane library and other sources,such as using a manual retrieval from relevant studies.After the initial scan of titles and abstracts,39 unrelated studies were excluded because they were not relevant to AD or they were duplicate publications.According to the inclusion standards set in advance,28publications were excluded.After our screening,18 articles on relevant single nucleotide polymorphisms(SNP)were included in this meta analysis.Eventually,38 researches investigating the SNP of rs3865444 and 4 researches investigating the SNP of rs3826656were included.The results of the forest plot suggest that in the general population,the minor allele(A allele)of CD33 rs3865444 has a protective effect on AD,which can reduce the risk of AD,OR=0.93,95%CI=[0.90,0.97].Considering the difference of ethnicity,we made subgroup analyses.Further subgroup analysis of the included population showed that the minor allele(A allele)of rs3865444 gene loci also had a protective effect in Caucasian populations,OR=0.91,95%CI=[0.89,0.93].In the Asian population,we found no association between A allele within rs3865444 and AD,OR=0.87,95%CI=[0.65,1.17].We did a research about the association between CD33 rs3826656 SNP and AD susceptibility in a cumulative meta-analysis.Among the 4 studies on rs3826656 SNP,3 were conducted in the Asian population and only one was performed in Caucasians.The pooled ORs identifed no correlation between G allele within rs3826656 and AD in the present meta-analysis,OR=0.94,95%CI=[0.62,1.41].Conclusions:The minor allele(A allele)of CD33 rs3865444 played a protective role in AD,and this protective role still existed in Caucasian population in the subgroup analysis.There were no association between the minor allele(G allele)of CD33 rs3826656 and AD.Further studies with large sample size should be done to confirm our fndings.