GSK3B基因3'-UTR多态性与阿尔茨海默病发病风险的相关性分析
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摘要
目的研究中国汉族人群中糖原合成酶激酶3β基因(GSK3B)3'端非翻译区(3'-UTR)基因多态性与阿尔茨海默病(AD)发病风险的相关性。方法采用直接测序的方法,对535例AD病例及464例正常对照的GSK3B基因3'-UTR单核苷酸多态性(SNPs)位点进行基因分型。结果 GSK3B基因3'-UTR各SNPs位点的等位基因频率和基因型分布在AD组和正常对照组之间的差异无统计学意义(P>0.05)。其中rs60393216、rs56728675和rs3732361存在强连锁不平衡,其构成的三种单体型的频率在AD组和正常对照组之间的差异无统计学意义(P>0.05)。结论 GSK3B基因3'-UTR多态性与中国汉族人群AD发病风险无关。
Objective To determine whether the single nucleotide polymorphisms(SNPs) in 3'-untranslated region(3'-UTR) of glycogen synthase kinase-3 beta gene(GSK3 B) is associated with Alzheimer's disease(AD) in Chinese Han population. Method Genotypes were determined by direct sequencing technology in 535 patients with AD and 464 controls. Results There was no significant difference in the allele or genotype frequencies for the SNPs in the 3'-UTR of GSK3 B gene between AD patients and controls(P>0.05). There was a strong linkage disequilibrium among rs60393216, rs5672867 and rs3732361. The frequencies of haplotypes derived from these three SNPs showed no difference between AD patients and controls(P>0.05). Conclusion Our results do not support a genetic association between the polymorphisms in the 3'-UTR of GSK3 B and the risk of AD in Han Chinese.
Objective To determine whether the single nucleotide polymorphisms(SNPs) in 3'-untranslated region(3'-UTR) of glycogen synthase kinase-3 beta gene(GSK3 B) is associated with Alzheimer's disease(AD) in Chinese Han population. Method Genotypes were determined by direct sequencing technology in 535 patients with AD and 464 controls. Results There was no significant difference in the allele or genotype frequencies for the SNPs in the 3'-UTR of GSK3 B gene between AD patients and controls(P>0.05). There was a strong linkage disequilibrium among rs60393216, rs5672867 and rs3732361. The frequencies of haplotypes derived from these three SNPs showed no difference between AD patients and controls(P>0.05). Conclusion Our results do not support a genetic association between the polymorphisms in the 3'-UTR of GSK3 B and the risk of AD in Han Chinese.
引文
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[15]Lambert JC,Luedecking-Zimmer E,Merrot S,et al.Association of3'-UTR polymorphisms of the oxidised LDL receptor 1(OLR1)gene with Alzheimer's disease[J].J Med Genet,2003,40(6):424-430.
[16]Luedecking-Zimmer E,DeKosky ST,Chen Q,et al.Investigation of oxidized LDL-receptor 1(OLR1)as the candidate gene for Alzheimer's disease on chromosome 12[J].Hum Genet,2002,111(4-5):443-451.
[17]Delay C,Calon F,Mathews P,et al.Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function[J].Mol Neurodegener,2011,6:70.
[18]Mateo I,Vazquez-Higuera JL,Sanchez-Juan P,et al.Epistasis between tau phosphorylation regulating genes(CDK5R1 and GSK-3beta)and Alzheimer's disease risk[J].Acta Neurol Scand,2009,120(2):130-133.
[19]Kwok JB,Loy CT,Hamilton G,et al.Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease[J].Ann Neurol,2008,64(4):446-454.
[20]Hohman TJ,Koran ME,Thornton-Wells TA,et al.Interactions between GSK3beta and amyloid genes explain variance in amyloid burden[J].Neurobiol Aging,2014,35(3):460-465.
[21]Hohman TJ,Chibnik L,Bush WS,et al.GSK3beta Interactions with amyloid genes:an autopsy verification and extension[J].Neurotox Res,2015,28(3):232-238.
[2]Hooper C,Killick R,Lovestone S.The GSK3 hypothesis of Alzheimer's disease[J].J Neurochem,2008,104(6):1433-1439.
[3]王芬,秦伟,魏翠柏,等.GSK3B基因启动子区多态性与中国北方汉族人群阿尔茨海默病的相关分析[J].神经疾病与精神卫生,2013,13(4):331-334.
[4]McKhann G,Drachman D,Folstein M,et al.Clinical diagnosis of Alzheimer's disease:report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease[J].Neurology,1984,34(7):939-944.
[5]McKhann GM,Knopman DS,Chertkow H,et al.The diagnosis of dementia due to Alzheimer's disease:recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):263-269.
[6]Hixson JE,Vernier DT.Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI[J].J Lipid Res,1990,31(3):545-548.
[7]Zeng X,Tamai K,Doble B,et al.A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation[J].Nature,2005,438(7069):873-877.
[8]Steinbrecher KA,Wilson W 3rd,Cogswell PC,et al.Glycogen synthase kinase 3beta functions to specify gene-specific,NF-kappaB-dependent transcription[J].Mol Cell Biol,2005,25(19):8444-8455.
[9]Hernandez F,Gomez de Barreda E,Fuster-Matanzo A,et al.GSK3:a possible link between beta amyloid peptide and tau protein[J].Exp Neurol,2010,223(2):322-325.
[10]Russ C,Lovestone S,Powell JF.Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer's disease[J].Mol Psychiatry,2001,6(3):320-324.
[11]Mateo I,Infante J,Llorca J,et al.Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer's disease[J].Dement Geriatr Cogn Disord,2006,21(4):228-232.
[12]Zhang N,Yu JT,Yang Y,et al.Association analysis of GSK3B and MAPT polymorphisms with Alzheimer's disease in Han Chinese[J].Brain Res,2011,1391:147-153.
[13]Kettunen P,Larsson S,Holmgren S,et al.Genetic variants of GSK3Bare associated with biomarkers for Alzheimer's disease and cognitive function[J].J Alzheimers Dis,2015,44(4):1313-1322.
[14]Li J,Zeng F,Deng J,et al.The association between single nucleotide polymorphisms of GSK 3beta gene and sporadic Alzheimer's disease in a cohort of southern Chinese Han population[J].Neurotox Res,2014,26(4):447-453.
[15]Lambert JC,Luedecking-Zimmer E,Merrot S,et al.Association of3'-UTR polymorphisms of the oxidised LDL receptor 1(OLR1)gene with Alzheimer's disease[J].J Med Genet,2003,40(6):424-430.
[16]Luedecking-Zimmer E,DeKosky ST,Chen Q,et al.Investigation of oxidized LDL-receptor 1(OLR1)as the candidate gene for Alzheimer's disease on chromosome 12[J].Hum Genet,2002,111(4-5):443-451.
[17]Delay C,Calon F,Mathews P,et al.Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function[J].Mol Neurodegener,2011,6:70.
[18]Mateo I,Vazquez-Higuera JL,Sanchez-Juan P,et al.Epistasis between tau phosphorylation regulating genes(CDK5R1 and GSK-3beta)and Alzheimer's disease risk[J].Acta Neurol Scand,2009,120(2):130-133.
[19]Kwok JB,Loy CT,Hamilton G,et al.Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease[J].Ann Neurol,2008,64(4):446-454.
[20]Hohman TJ,Koran ME,Thornton-Wells TA,et al.Interactions between GSK3beta and amyloid genes explain variance in amyloid burden[J].Neurobiol Aging,2014,35(3):460-465.
[21]Hohman TJ,Chibnik L,Bush WS,et al.GSK3beta Interactions with amyloid genes:an autopsy verification and extension[J].Neurotox Res,2015,28(3):232-238.