Association Of Hla-drb1 And Tmem106b Polymorphism With Late-onset Alzheimer's Disease In Northern Han Chinese Population

Background: Alzheimer's disease(AD)is a complex and multifactorial neurodegenerative disease.Researches showed that Apolipoprotein E(APOE)gene was recognized as a susceptibility gene associated with the pathogenesis of AD.But the APOE gene does not explain all sporadic AD;it was associated with only 50% of lateonset Alzheimer's disease(Late-onset Alzheimer's disease,LOAD).Therefore,it is suggested that there are other genetic risk factors involved in the pathogenesis of AD,and other genetic risk factors should be further explored.In recent years,Genome-wide association studies(GWAS)as genetic association studies have shed light on the genetic basis of LOAD,which can discover more several genes and/or loci involved in the susceptibility to suffer this disease.Since variants and their frequencies of candidate genes in various ethnic groups might be different,further replication became the urgent task to be performed in other ethnic cohorts.Therefore,the results of these studies need to be further verified in other ethnic groups,so as to obtain reliable conclusions.One recent GWAS been performed in LOAD and tagged HLA-DRB1 rs9271192 as new susceptibility loci in Caucasians.So,it needs to be validated in Chinese Han population because of the distinctions in HLA-DRB1 among different races.Recently,one GWAS and large case–control studies in FTLD-TDP identified TMEM106 B variants as novel players in the pathogenic cascade of FTLD.Many autopsy studies had found that 55% of patients with FTLD and 25-30% of patients with AD harbor TAR DNA-binding protein 43(TAP-43)immunoreactive pathological changes in their brains.In addition,FTLD and AD have similar characteristic pathological changes: neurofibrillary tangles caused by abnormal phosphorylation of tau.Accordingly,AD and FTLD may have some shared risk factors and/or common pathogenic mechanisms,we also further verified it in Chinese Han population.In order to obtain the relationship between HLA-DRB1,TMEM106 B and the pathogenesis of LOAD is more accurate and objective evaluation,finally we use use Meta-analysis(Meta-analysis),to evaluate the results of objective consistency.Objective: Genome-wide association studies(GWAS)have identified one singlenucleotide polymorphism(SNP)rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease(AD)in Caucasians.And recent large genome-wide associationObjective: Genome-wide association studies(GWAS)have identified one singlenucleotide polymorphism(SNP)rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease(AD)in Caucasians.And recent large genome-wide associationstudies have found variants in TMEM106B(SNP rs1990622)as a strong risk factor for frontotemporal lobar degeneration.Moreover,the TMEM106 B risk variant is also implicated in the pathologic presentation of Alzheimer's disease(AD).We evaluated the association between HLA-DRB1(rs9271192)and TMEM106B(rs1990622)polymorphism with late-onset AD in a Northern Han Chinese population.Methods: We evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD(LOAD)in a Northern Han Chinese population.LOAD patients and sex-and age-matched healthy controls were recruited.Genotyping for the HLA-DRB1(rs9271192)and TMEM106B(rs1990622)were carried out between the two groups by a patent-pending technology of SNP scan.Genotype and allele distributions were compared in the two groups by using the x2 test.The intension of association between SNPs and LOAD was estimated with the odds ratios(ORs)with 95% confidence intervals(CIs)by binary logistic regression,justed for age(age at examination for control subjects),gender and APOE ?4 status.We carried out a systematic literature search of MEDLINE,EMBASE and the Cochrane library for studies published in the period from January 1995 to April 2016 to investigate the association between the HLA-DRB1 rs9271192,TMEM106B(rs1990622)polymorphism and LOAD.The key search terms including HLA-DRB1,HLA-DRB5–DRB1,rs9271192,TMEM106 B,rs1990622,Alzheimer's disease,and AD,combined with Boolean operators as appropriate.Finally,we pooled our data with the results from meta-analysis of 82501 individuals and other reports about HLA-DRB1(rs9271192)and LOAD.Results:1?General characteristics of the study population.There was no significant difference in gender and age between the LOAD group and the control group(HLADRB1: P = 0.19,P = 0.07;TMEM106B: P = 0.08;P = 0.08).There was a significant difference between the two groups in the MMSE scale score(HLA-DRB1: P < 0.001;TMEM106B: P=0.001).In the LOAD group and the control group,the distribution of APOE ?4 allele was significantly different(HLA-DRB1:P<0.001;TMEM106B: P<0.001).2?Genotype and allele distribution of HLA-DRB1 and TMEM106 B gene polymorphism in LOAD and control groups.The results showed that HLA-DRB1 rs9271192 was associated with LOAD(genotype P = 0.02,allele P = 0.04).And rs9271192 polymorphisms in HLA-DRB1 reach significant differences in the allele frequencies in the total sample(P = 0.043).Higher frequencies of the minor allele(C)were observed in patients with LOAD compared with control subjects(19.04% vs.16.74%).When the genotype and allele distribution were stratified by the APOE ?4 allelestatus,we observed significant differences in the genotype frequencies in the APOE ?4 non-carriers(P = 0.002).In APOE ?4 allele carriers,the genotype and allele distribution of rs9271192 between LOAD patients and controls was no significantly different(P = 0.70,P =0.96,respectively).The rs1990622 polymorphisms in TMEM106 B have not significant differences in the genotype frequencies in the total sample(P = 0.07).And rs1990622 polymorphisms in TMEM106 B did not reach significant differences in the allele frequencies in the total sample(P = 0.24).When the genotype and allele distribution were stratified by the APOE e4 allele status,we observed significant differences in the APOE?4 allele carriers(P = 0.02,P = 0.003,respectively).In APOE ?4 allele noncarriers,the genotypes distribution of rs1990622 between LOAD patients and controls was significantly different(P = 0.03).2?We further investigated the distributions of the rs9271192 and rs1990622 polymorphism in multivariate logistic regression analysis(adjusted for age,gender,and the APOE ?4 allele status for the total sample;adjusted for age and gender for the subsets).The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample(P = 0.004,OR =2.07,95%CI = 1.26-3.43).When these data were stratified by APOE?4 status,the observed association was confined to APOE?4 noncarriers(Additive model: P=0.05,OR =1.19,95%CI =1.00-1.42;recessive model: P <0.001,OR = 2.60,95%CI =1.52-4.57).Furthermore,meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD(OR = 1.12,95%CI = 1.08–1.15).To summarize,the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD.We also further investigated the distributions of the rs1990622 polymorphism in multivariate logistic regression analysis(adjusted for age,gender,and APOE ?4 allele status for the total sample;adjusted for age and gender for the subsets).The results revealed no significant differences after adjusted for age,gender,and the APOE?4 allele status for the total sample in dominant,recessive and additive model(dominant model: P = 0.15,OR=1.21,95 % CI=0.95–1.41;recessive model: P = 0.78,OR=0.98,95 % CI=0.85–1.13;additive model: P = 0.59,OR=1.03,95%CI=0.93–1.14).However,the results revealed significant differences in the APOE?4 allele carriers after adjusted for only age and gender in recessive model(P = 0.006,OR =1.53,95 % CI 1.04–2.23).Conclusions: Our current study have provided a convincing statistical support for an association between the HLA-DRB1 polymorphism and LOAD,the carriage of C allele of the rs9271192 is associated with increased risk of LOAD in a Northern Han Chinesepopulation.In our large case–control analysis,we first evaluated the association between well-known TMEM106 B rs1990622 polymorphisms and LOAD risk in our total samples and found no association between TMEM106 B rs1990622 polymorphism and LOAD in a Northern Han Chinese population.In our study suggested that TMEM106 B rs1990622 polymorphism might modify the risk of LOAD in interaction with the APOE ?4 allele in Northern Han Chinese population.