Association Analysis Of Late-onset Alzheimer’s Disease And Susceptibility Genes In Chinese Han Population

Background:Alzheimer’s disease (AD) is the most common type of dementia which always has an insidious onset. It is an age-related neurodegenerative disease with progressive cognitive dysfunction and memory loss as the major manifestations. The etiology and pathogenesis of AD is still unknown. As a complex disease, the effects of genetic factors in the pathogenesis of AD are grasping more and more attention. Familial Alzheimer’s disease (FAD) is clearly associated with APP, PSEN1and PSEN2. APOE is the only confirmed risk gene for sporadic AD (SAD) while other susceptibility genes remain to be further verified. Late-onset Alzheimer’s disease (LOAD) refers to patients with age of onset after65year-old, which always lack of family history. Recently, genome-wide association studies have discovered many new susceptibility genes for LOAD and following a number of validation studies from different races. But researches above can’t make consistent conclusions and always select limited number of loci. There are no researches using high throughput methods to verify multi-loci in Chinese Han LOAD patients.Objective:To explore the association between LOAD and susceptibility genes in Chinese Han population through verifying58AD-related susceptibility gene polymorphic loci in patients with LOAD.Methods:58polymorphic loci were genotyped in239cases of LOAD and207normal controls with the aid of MALDI-TOF MassARRAY. We compared differences in allele and genotype frequency in the case and control group. The linkage disequilibrium analysis and haplotype analysis were further performed.Results:1、The number of APOE-epsilon4carriers in LOAD group was larger than in normal controls. The difference was statistically significant (P=0.002, OR=2.011).2, The rs9331888-G of CLU gene, rs6691117-G of CR1gene, rs3851179-A and rs10792832-A of PICALM gene were higher in nomal controls. The differences were statistically significant (P=0.007, OR=0.673; P=0.010, OR=0.650; P=0.025, OR=0.716; P=0.030, OR=0.728).The rs9271192-C of HLA-DRB5/DRB were higher in LOAD group (P=0.015, OR=1.596); The rs592297-C of PICALM gene, rs15758-G and rs11556505-T of TOMM40gene together with rs1562990-C of MS4A/4EA gene cluster were higher in LOAD group. The differences were statistically significant (P=0.032, OR=1.380; P=0.028, OR=1.430; P=0.003, OR=1.869; P=0.049, OR=1.347), but there were no statistical differences after adusting age, gender and APOE-epsilon4status.For the remaining43loci according with Hardy-Weinberg equilibrium, the distribution of allele and genotype frequency between the two groups had no statistical differences after adusting confounding factors and stratifying by APOE-epsilon4status and gender (P>0.05)3、A haplotype GCCAC in CLU gene and a haplotype AGTACC located in APOE/TOMM40were higherer in LOAD group (P=0.014, OR=1.766;P=0.0170, OR=1.770)Conclusion: 1、APOE gene polymorphism is associated with the the susceptibility of LOAD in the Chinese Han population, carrying APOE-epsilon4can obviously increase the risk of the disease.2、rs9331888-G of CLU gene, rs6691117-G of CR1gene, rs3851179-A and rs10792832-A of PICALM gene can decrease the risk of LOAD. rs9271192-C of HLA-DRB5/DRB1gene can increase the risk of LOAD.rs592297-C of PICALM gene, rs157581-G and rs11556505-T of TOMM40gene together with rs1562990-C of MS4A/4EA gene may be risk factors of LOAD.3、A haplotype GCCAC in CLU gene and a haplotype AGTACC located in APOE/TOMM40can increase the risk of LOAD.