FERMT2 Rs17125944 Polymorphism With Alzheimer’s Disease Risk In The Northern Han Chinese

Objective:Alzheimer’s disease(AD)is a progressive neurological disorder and a leading cause of dementia among elderly people,which is characterized by the deterioration of a patient’s cognitive and functional abilities.Its two pathological hallmarks in brain are extracellular amyloid plaques,which are deposits of amyloid β(Aβ)peptide,and intracellular neurofibrillary tangles(NFTs),which are formed by the microtubule-associated protein tau.According to the age of onset,AD contains early-onset Alzheimer disease(EOAD)and 1ate-onset Alzheimer disease(LOAD).And LOAD is much more common.In the mode of inheritance,EOAD usually follows an autosomal dominant inheritance pattern.LOAD is much more complex with involvement of gene and environment interactions.Until now,apolipoprotein E(APOE)is the major risk factor for LOAD,however,it does not explain the whole genetic diversity of AD.Many candidate genes are identified that contribute to LOAD risk.The single nucleotide polymorphisms(SNP),rs17125944 in the FERMT2 gene on chromosome 14q22.1 was firstly found to be associated with LOAD in the completion of meta-analysis with 74,046 individuals from Caucasians.As a new susceptibility locus,rs17125944 reached genome-wide significance in the combined discovery and replication analysis.Meanwhile,FERMT2,were found to modify Tau toxicity and take part in APP metabolism.Then three studies have replicated the association of rs17125944 polymorphism with the risk for LOAD.Ruiz et al.validated the association in Spanish,and Xiao et al.verified the association in Southern Han Chinese.However,Jiao et al.failed to replicate the association of rs17125944 polymorphism with LOAD in another Chinese population.Since there were different results about the association of rs17125944 with LOAD risk in Han Chinese,it was essential to confirm the genetic association in other Chinese groups.So we validate the association of the rs17125944 polymorphism with LOAD risk in the northern Han Chinese.Methods:We recruited a case–control study of 2338 Han Chinese subjects(984 cases and 1354 age-and gender-matched controls).All the participants were Northern Han Chinese.The patients of LOAD were recruited from the Department of Neurology at Qingdao Municipal Hospital,and several other hospitals in Shandong Province.The probable AD was clinically diagnosed on the basis of the criteria of National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association(NINCDS-ADRDA)by at least two neurologists.The control participants were recruited from the Health Examination Center of the Qingdao Municipal Hospital.The healthy controls were proved healthy through medical history,general examinations,laboratory examinations and Mini Mental State Examination(MMSE)(score≥28).From a recent meta-analysis of genome-wide association studies(GWAS)in population of Caucasian,several new susceptibility loci are identified to have relationship with LOAD.And we choose the rs17125944 in the FERMT2 for the object of our study.DNA was extracted from the peripheral blood of participants using the Wizard genomic DNA purification kit(Cat.#A1125,Promega,USA).The rs17125944 polymorphism was genotyped using the means of SNPscan TM kit(Cat#: G0104 K,Genesky Biotechnologies Inc.,Shanghai,China).And the kit was a patent-pending technology from Genesky Biotechnologies Inc.,which was developed on double ligation and multiplex fluorescent polymerase chain reaction(PCR).Data analysis was obtained using Gene Mapper 4.1(Applied Biosystems,USA).APOE genotype was measured by the improved multiplex ligase detection reaction(i MLDR)method,which was supported from the Shanghai Genesky Biotechnology Company.The Hardy-Weinberg equilibrium(HWE)was calculated for SNP using genotype data from AD patients and controls.Differences of the characteristics between cases and controls were examined using the Student t-test or the Chi-square test.Genotype and allele distributions were compared using the Chi-square test.Differences in allele and genotype distribution between cases and controls were analyzed using logistic regression adjusted for non-genetic covariates and APOEε4 status under various genetic models that were defined as 1(TC +CC)versus 0(TT)for dominant,1(CC)versus 0(TT +TC)for recessive,and 0(TT)versus 1(TC)versus 2(CC)for additive.The p value,odds ratios(OR)and 95% confidence intervals(CI)were accounted.The statistical analyses were performed by SPSS 16.0 software.The criterion for significant difference was P < 0.05.In addition,we also performed a meta-analysis in the present related studies in different population and our study to detect the relationship.Results:There were no significant differences between patients of LOAD and control participants(genotype P = 0.953;allele P =0.975,OR = 0.998,95% CI = 0.868-1.146).Then we stratified these data through the presence/absence of the APOE ε4.However,no significance was observed in both subjects with APOEε4 allele(genotype: P = 0.398;allele: P = 0.377,OR = 1.151,95% CI = 0.842-1.572)and without the APOE ε4 allele(genotype: P = 0.395;allele: P = 0.586,OR = 0.957,95% CI = 0.816-1.122).Furthermore,by multivariate logistic regression,there was also no association between the rs17125944 polymorphism and LOAD(dominant model: P = 0.766,OR = 0.974,95%CI = 0.822-1.156;additive model: P = 0.937,OR = 0.994,95% CI = 0.863-1.146;recessive model: P = 0.647,OR= 1.094,95% CI = 0.746-1.603)after adjusting for age,gender,and the APOE ε4 allele carrier status.The meta-analysis showed that the C allele is the risk factor for LOAD in Caucasian group(OR = 1.15,95 % CI = 1.10-1.20)and combined population(OR = 1.13,95 % CI = 1.08-1.19).And the heterogeneity(I2 = 8.0%)of these studies is not notable.While in Chinese population,the C allele is not associated with increased risk of LOAD(OR = 1.07,95% CI = 0.89-1.28).Conclusions:Our study showed that the FERMT2 rs17125944 polymorphism is no association with LOAD in northern Han Chinese population.And the result needs further confirmation by studies in larger sample sizes and different ethnic groups.Meanwhile,it is necessary to clarify the exact relationship between FERMT2 and Tau toxicity and APP metabolism in human.