Association Between Glycogen Synthase Kinase-3β Genetic Polymorphism Or Its Haplotypes And Alzheimer's Disease

Background and objective:Alzheimer's disease (AD) is a degenerative disorders characterized with progressively deteriorated memory and cognition. The main pathological features are the presence ofβ-amyloid protein in senile plaques and neurofibrillary tangles composed of intraneuronal abnormal hyperphosphorylation of tau which accumulates into double-helical filaments (PHF). Although the exact pathogenesis of Alzheimer's disease has not yet been clarified, recent studies have shown that glycogen synthase kinase-3(3 (GSK-3β) is closely related to tau hyperphosp-horylation, Aβformation, oxidative stress, inflammation, apoptosis and reduced synthesis of acetylcholine, which are pathological changes of AD. There have already some research on the association between the polymorphism of rs334558 loci of GSK-3βand AD abroad suggesting that GSK-3βand its gene polymorphism may play an important role in the pathogenesis of AD. There has not any relevant research reported about Chinese yet. This study was To identify the genotypes, alleles and haplotype frequencies of rs334558 and rs6438552 of GSK-3βin the Hunan Han population, discuss the association between GSK-3(3 and AD, explore genetic evidence of AD and develop more approaches for early diagnosis of AD.Methodwe performed case-control study to analyze the distribution and interaction of rs334558 and rs6438552 of GSK-3(3 allele, genotype and haplotype frequencies in Hunan Han population comprising 203 sporadic AD patients and 239 healthy controls by polymerase chain reaction(PCR) and restriction fragment length polymorphisms(RFLP).Result1. The frequency of CC, TC, TT genotype of GSK-3p in the rs3345582 locus were 27.1%,60.4%,12.5% respectively among AD group, and 2.1%,83.7%,14.2% respectively among non-dementia controls. CC genotype in the AD group are significantly higher than in the control (P <0.05), which suggested that those who bring C/C genotype have a higher risk of AD disease. Allele analysis showed the C allele frequency in AD Group (57.3%) was significantly higher the control (44.0%). The difference was significant (OR =1.709, P<0.05), suggesting that those carrying C allele may have a higher risk of AD.2. The frequency of C/C, T/C, T/T genotype of GSK-3βin the rs6438552 locus were 26.4%,53.5%,20.1% respectively among AD group, and 25.5%,60.3%,14.2% respectively among non-dementia controls. The genotypes between the AD group and the control group have no significantly difference in the distribution (P>0.05). The allele analysis showed that C allele frequency in AD Group (53.1%) was significantly higher than in the control (44.3%). The difference was significant (OR =1.423, P<0.05), suggesting that those carrying C allele may have a higher risk of AD.3. The linkage disequilibrium and haplotype analysis of the polymorphism of the rs334558 and rs6438552 of GSK-3β: the SHEsis software show there are high degree of linkage disequilibrium between the polymorphism of two loci (D'= 0.745). The HaploView software showed that haplotype C-T in AD group was significantly higher than the control (OR= 3.208, P<0.05), suggesting that those carrying haplotype C-T have a higher risk of AD. Haplotype T-C was significantly lower than the control group (OR= 0.263, P<0.05), suggesting that those carrying haplotype T-C have a lower risk of AD.Conclusion:1. CC genotype and C allele in the rs334558 loci of GSK-3(3 may be associated with Hunan Han population of China in the pathogenesis of AD.2. C allele in rs6438552 loci of GSK-3(3 may be associated with Hunan Han population of China in the pathogenesis of AD, but CC genotype may not.3. The haplotype C-T or T-C in rs334558 and rs6438552 loci of GSK-3βin Hunan Han population of China may be associated with the pathogenesis of AD.