聚集素基因多态性及外周血聚集素水平与阿尔茨海默病相关性研究
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摘要
目的探讨西南地区汉族人群聚集素(CLU)基因多态性及外周血CLU与阿尔茨海默病(AD)的关系。方法纳入AD患者108例(AD组),健康对照115例(对照组),应用SNaPshot SNP分型技术对入选11个位点进行分型,采用双抗体夹心酶联免疫吸附试验(ELISA)检测AD组与对照组外周血清CLU水平。结果AD组血清CLU水平显著高于对照组,差异有统计学意义(P=0.001)。CLU基因SNP位点rs3087554在显性模型下差异有统计学意义(P=0.037,OR=0.523,95%CI=0.284~0.962),其余8个位点各基因型和等位基因在病例组和对照组的分布无差异。CLU基因型和血清CLU水平相关性分析未发现显著性差异。结论AD患者血浆CLU水平较对照组明显升高,CLU可能在AD的发生发展中发挥作用。CLU rs3087554位点CC或CT基因型可能是AD的保护性因素。未发现其他8个SNP多态性与疾病的联系。
Objective To assess the correlation between the clusterin(CLU)level and its gene polymorphism and Alzheimer′s disease(AD)among ethnic Han Chinese in southwest of China.Methods A total of108 patients with AD(AD group)and 115 healthy controls(control group)were enrolled in this study.SNaPshot SNP typing was used to genotype 11 SNP.Serum levels of CLU were detected by ELISA.Results The clustrin level of peripheral blood in AD group was significantly higher than that in the control group(P=0.001).There were statistically significant differences of the rs3087554 locus of CLU gene in the dominant model(P=0.037,OR=0.523,95%CI=0.284-0.962).There was no significant difference in the distribution of other eight loci genotypes and alleles between AD group and control group.No significant association were found between genotypes and serum CLU levels.Conclusion The plasma levels of CLU in AD patients are significantly higher than those in control group.CLU may play a role in the occurrence and development of AD.CC or CT genotype of rs3087554 in CLU gene may be a protective factor of AD.No association was found between the other eight SNPs and AD disease.
Objective To assess the correlation between the clusterin(CLU)level and its gene polymorphism and Alzheimer′s disease(AD)among ethnic Han Chinese in southwest of China.Methods A total of108 patients with AD(AD group)and 115 healthy controls(control group)were enrolled in this study.SNaPshot SNP typing was used to genotype 11 SNP.Serum levels of CLU were detected by ELISA.Results The clustrin level of peripheral blood in AD group was significantly higher than that in the control group(P=0.001).There were statistically significant differences of the rs3087554 locus of CLU gene in the dominant model(P=0.037,OR=0.523,95%CI=0.284-0.962).There was no significant difference in the distribution of other eight loci genotypes and alleles between AD group and control group.No significant association were found between genotypes and serum CLU levels.Conclusion The plasma levels of CLU in AD patients are significantly higher than those in control group.CLU may play a role in the occurrence and development of AD.CC or CT genotype of rs3087554 in CLU gene may be a protective factor of AD.No association was found between the other eight SNPs and AD disease.
引文
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[18]ZHENG W,YAO M,SAI W,et al.Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma[J].Tumor Biol,2016,37(1):999-1008.
[19]MIYAKE H,HARA I,KAMIDONO S,et al.Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model[J].Clin Cancer Res,2001,7(12):4245-4252.
[20]LI Y,LU J,SHAN Z,et al.Clusterin induced by N,N′-Dinitrosopiperazine is involved in nasopharyngeal carcinoma metastasis[J].Oncotarget,2016,7(5):5548-5563.
[21]PRIKRYLOVVH,HNYKOVE,MAREJ,et al.Clusterin CSF levels in differential diagnosis of neurodegenerative disorders[J].J Neurol Sci,2016,361:117-121.
[22]THAMBISETTY M,BEASON-HELD L L,AN Y,et al.Alzheimer risk variant CLU and brain function during aging[J].Alzheimers Dement,2013,73(5):399.
[23]CAI R,JING H,JIE S,et al.Plasma clusterin and the CLU gene rs11136000variant are associated with mild cognitive impairment in type 2diabetic patients[J].Front Aging Neurosci,2016,8:179.
[24]YU J T,LI L,ZHU Q X,et al.Implcation of CLU gene polymorphisms in Chinese patients with Alzheimers disease[J].Clin Chim Acta,2010,411:1516-1519.
[25]DU W,TAN J,XU W,et al.Association between clusterin gene polymorphism rs11136000 and late-onset Alzheimer′s disease susceptibility:a review and metaanalysis of case-control studies[J].Exp Ther Med,2016,12(5):2915-2927.
[2]DULSAT,C.A report from the 65th annual meeting of the American Academy of Neurology(March 16-23,2013,San Diego,California,USA)[J].Drugs Today(Barc),2013,49(5):341-345.
[3]WANNER M,KESSLER J,MARTIG J,et al.Amyloid deposition as the central event in the aetiology of Alzheimer′s disease[J].Trends Pharmacol Sci,1991,12(10):383.
[4]BLENNOW K,HAMPEL H.CSF markers for incipient Alzheimer′s disease[J].Lancet Neurol,2003,2(10):605-613.
[5]陈逸,张宝荣.阿尔茨海默病相关核心生物标志物研究进展[J].生命科学,2014,26(1):2-8.
[6]LARS M.ITTNER,JRGEN G.Amyloid-βand tau:a toxic pas de deux in Alzheimer′s disease[J].Nat Rev Neurosci,2011,12(2):65.
[7]GOATE A,CHARTIER-HARLIN M C,MULLAN M,et al.Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer′s disease[J].Nature,1991,349(6311):704-706.
[8]BRUNI A C.Cloning of a gene bearing missense mutations in early onset familial Alzheimer′s disease:a Calabrian study[J].Funct Neurol,1998,13(3):257-261.
[9]ROGAEV E I,SHERRINGTON R,ROGAEVA E A,et al.Familial Alzheimer′s disease in kindreds with missense mutations in agene on chromosome 1related to the Alzheimer′s disease type 3gene[J].Nature,1995,376(6543):775-778.
[10]OSSENKOPPELE R,FLIER W M V D,ZWAN M D,et al.Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia[J].Neurology,2013,80(4):359-365.
[11]LAMBERT J C,HEATH S,EVEN G,et al.Genomewide association study identifies variants at CLU and CR1associated with Alzheimer′s disease[J].Nature Genetics,2009,41(10):1094-1099.
[12]HAROLD D,ABRAHAM R,HOLLINGWORTH P,et al.Erratum:genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer′s disease[J].Nat Genet,2009,41(10):1094.
[13]BLASCHUKO,BURDZYAK,FRITZIB.Purification and characterization of a cell aggregating factor(clusterin),the major glycoprotein in ramretetestis fluid[J].Biol Chem,1983,258(12):7714.
[14]MULLAN G M,MCENENY J,FUCHS M,et al.Plasma clusterin levels and the rs11136000genotype in individuals with mild cognitive impairment and Alzheimer′s disease[J].Curr Alzheimer Res,2013,10(9):973.
[15]MINERS J S,CLARKE P,LOVE S.Clusterin levels are increased in Alzheimer′s disease and influence the regional distribution of Aβ[J].Brain Pathol,2016,27(3):305-313.
[16]PLUTA R.Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer′s disease brain.[J].Curr Neurovas Res,2007,4(2):121.
[17]WONG P,PINEAULT J,LAKINS J,et al.Genomic organization and expression of the rat TRPM-2(clusterin)gene,agene implicated in apoptosis[J].J Biol Chem,1993,268(7):5021.
[18]ZHENG W,YAO M,SAI W,et al.Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma[J].Tumor Biol,2016,37(1):999-1008.
[19]MIYAKE H,HARA I,KAMIDONO S,et al.Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model[J].Clin Cancer Res,2001,7(12):4245-4252.
[20]LI Y,LU J,SHAN Z,et al.Clusterin induced by N,N′-Dinitrosopiperazine is involved in nasopharyngeal carcinoma metastasis[J].Oncotarget,2016,7(5):5548-5563.
[21]PRIKRYLOVVH,HNYKOVE,MAREJ,et al.Clusterin CSF levels in differential diagnosis of neurodegenerative disorders[J].J Neurol Sci,2016,361:117-121.
[22]THAMBISETTY M,BEASON-HELD L L,AN Y,et al.Alzheimer risk variant CLU and brain function during aging[J].Alzheimers Dement,2013,73(5):399.
[23]CAI R,JING H,JIE S,et al.Plasma clusterin and the CLU gene rs11136000variant are associated with mild cognitive impairment in type 2diabetic patients[J].Front Aging Neurosci,2016,8:179.
[24]YU J T,LI L,ZHU Q X,et al.Implcation of CLU gene polymorphisms in Chinese patients with Alzheimers disease[J].Clin Chim Acta,2010,411:1516-1519.
[25]DU W,TAN J,XU W,et al.Association between clusterin gene polymorphism rs11136000 and late-onset Alzheimer′s disease susceptibility:a review and metaanalysis of case-control studies[J].Exp Ther Med,2016,12(5):2915-2927.