Orexin-2 Receptor Gene Polymorphisms And Alzheimer's Disease Correlation And Bioinformatics Analysis

Part?: Orexin-2 Receptor Gene Polymorphisms and Alzheimer'sDisease Correlation ObjectiveTo investigate the association between orexin-2 receptor(OX2R)gene polymorphisms and Alzheimer's disease,and to analyze its relationship with orexin levels,sleep quality,and disease severity.Materials and methodsIn this study,a case-control study was used.350 patients with Alzheimer's disease were recruited as the study group and 350 healthy subjects were the control group.The general demographic data were collected.Peripheral blood samples were collected for DNA extraction,and 6 polymorphic sites of OX2 R gene and Apo E genotyping were uniformly detected.Simultaneously detect serum orexin levels.All subjects underwent a Mini-Mental State Examination(MMSE)scale,and the study group used a BPRS scale and a CDR score to grade the degree of dementia.According to the sleep characteristics of AD patients,the Pittsburgh Sleep Quality Index(PSQI)scale and the Epworth Sleepiness(ESS)scale were used to assess the quality of sleep and daytime sleepiness.All data were analyzed using SPSS19.0 statistical software.Hardy-Weinberg's law of genetic equilibrium is used to analyze the population representativeness of sampled genotypes.The normal distribution of measurement data is expressed as: The t-test is used to compare the mean of the two samples;the chi-square test is used tocompare the data between the two groups;P<0.05 is considered statistically significant.A multivariate logistic regression model using SNPStats online software was used to assess the association between SNPs genotype and risk of AD in the five genetic models.Multivariate logistic regression analysis was used to analyze the effect of genetic polymorphisms and other risk factors on the onset of AD;Linkage disequilibrium software(Haploview 4.2)was used to analyze the linkage disequilibrium between single nucleotide polymorphism sites;the Pearson coefficient was used.To evaluate the correlation between serum orexin levels and the severity of dementia and sleep quality.Results1.Apo E gene polymorphism in Chinese Han population in northern China is associated with LOAD,and the risk of LOAD in carriers of Apo E?4 gene is significantly increased.2.OX2 R gene rs2653349 and rs2292041 polymorphisms may be associated with LOAD,but may not be related to the severity.The A allele at these two loci may be a risk factor for LOAD.3.Logistic regression analysis of all factors showed that age,AD family history,hypertension,Apo E?4gene and rs2653349(GA + AA)genotypes were independent risk factors for AD.Haplotype analysis revealed that rs2653349+rs2292041 GA type,rs2653349+rs2292041+rs3122169 GAA,and ATC increased risk.4.The level of plasma orexin in the LOAD group was significantly increased,and with the severity of dementia and sleep quality was positively correlated,rs2653349 gene mutation can cause orexin levels.5.The SNP locus polymorphisms were not associated with the severity of dementia in AD patients;the rs2653349 and rs2292041 polymorphisms were associated with sleep quality in AD patients.ConclusionsThe OX2 R gene rs2653349 and rs2292041 polymorphisms in Han population in northern China may be related to LOAD,and the A allele may be a susceptibilityfactor for LOAD.Part?: Bioinformatics Analysis of OX2 R Gene PolymorphismObjectiveExplore the mechanism of OX2 R gene polymorphism,especially related sites on the impact of AD,and further bioinformatics tools for bioinformatics analysis of OX2R(HCRTR2)protein.For the correlation sites,we focus on local structure modeling to understand the change of structure before and after mutation,and analyze the possible influence of the change on its function.Materials and methodsThe bioinformatics tools were used to analyze the physicochemical properties,cellular localization and functional domains of OX2 R protein.The secondary structure,topological structure and tertiary structure of OX2 R protein were also analyzed.Using QUARK software,Corresponding amino acid sequences and protein structure differences,and to explore the mechanism of differences in functional effects of Alzheimer's disease.Results1.Rs2653349(Val308Ile)is located on the sixth transmembrane helix domain of this protein.Local protein modeling results show that when it changes from Val to Ile,its structure changes from random coil to double helix,and the folding angle occurs.Significant changes,combined with smaller binding sites,affect the binding of orexin and OX2 R and downstream signal transduction,and then cause A? amyloid deposition or sleep-wake disorders,eventually leading to the occurrence and development of AD.2.The rs2292041 locus is located between the sixth intron and intron 7,closer tothe seventh intron,closer to the branch point.It is speculated that mutation at this site may lead to splicing abnormalities,resulting in incorrect splicing sequences resulting in non-functional or protein-inactive m RNA.ConclusionsThe rs2653349 site polymorphism results in a change in the protein structure,which may lead to decreased ligand binding capacity of the receptor or the inability to generate normal downstream signals after binding;the rs2292041 locus polymorphism may lead to abnormal post-transcriptional splicing of the OX2 R gene,resulting in altered structure and activity of OX2 R.