Correlation Between HLA Gene Polymorphism And Structural Magnetic Resonance Imaging Changes In Key Brain Regions Of Alzheimer's Disease

Objective: There is accumulating evidence that the human leukocyte antigen(HLA)genes variants are associated with Alzheimer's disease(AD).Particularly,a large meta-analysis of genome-wide association studies(GWAS)identified a new susceptibility locus(rs9271192)in the HLA-DRB5–DRB1 region for AD.However,how they affect AD occurrence is still unknown.In this study,we firstly investigated the association of HLA genes variants and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative(ADNI)to explore the effects of HLA genes on AD pathogenesis.Our study aimed to provide preliminary evidences for early diagnoses and treatment of AD.METHODS: A total of 281 normal cognition(NC),483 mild cognitive impairment(MCI)individuals and 48 AD from the ADNI database is included in our analysis;We review the related literature and use the candidate gene strategy.The AD-associated alleles and loci are included in our analysis.The genotype data for participants included are extracted from the ADNI GWAS database.Hippocampus,parahippocampus,posterior cingulate,precuneus,middle temporal,entorhinal cortex and amygdala,which are affected by AD pathological lesions and validated via MRI studies,are selected as regions of interest(ROIs).The baseline MRI volumes or thicknesses of brain structures used in our study were from the ADNI dataset.The multiple linear regression models,which considered age,gender,education years,and Apo E ?4 status as covariates,were applied to examine the association between the selected single nucleotide polymorphisms(SNPs)or haplotype with AD-associated brain structures on MRI.In the present analysis,there were 718(NC = 257,MCI = 422,AD= 39)individuals included in the regional volume/thickness analysis.Analysis of the overall sample indicated significant correlation between positive HLA loci or haplotype and the development of AD.Thus,the next step we took was to further investigate the correlation between the MRI brain structures of each subgroup(CN,MCI,and AD)with the positive HLA loci or haplotype.We wanted to analyze and identify at which stage these variations impacted the pathological markers in the pathogenesis of AD.RESULTS: In total,281 cognitively normal(145 women,74.51±5.56 years),483 MCI(201 women,72.28±7.45 years)and 48 AD patients(18 women,75.51±9.23 years)were recruited in this study.As expected,the AD group had the highest frequency for the ?4allele within Apo E gene(44.8%),and the CN group had the lowest frequency(14.9%).Compared to CN and MCI subjects,AD dementia patients displayed the worst cognitive function based on these various neuropsychological scales(CDRSB,MMSE,ADAS-cog,etc.).Likewise,AD group showed the most severe atrophy in hippocampus,middle temporal and entorhinal cortex with the MRI method in comparison to MCI and CN individuals.(1)In hybrid population analysis,our results showed that TNF-? SNPs at rs2534672 and rs2395488 were significantly positively associated with the larger volume of the left middle temporal lobe(rs2534672: P=0.00035,Pc=0.004;rs2395488: P=0.0038,Pc=0.023)at baseline.Furthermore,we detected the two associations in MCI sub-group analysis,as well as the association of rs2534672 with the baseline volume of the left middle temporal lobe in NC sub-group analysis(2)In hybrid population analysis,our results showed a marginally significant association between HLA-A rs9260168 and the atrophy of the left parahippocampus(P=0.007,Pc=0.054),HLA-A rs3823342 and the atrophy of the left parahippocampus(P=0.014,Pc=0.054),rs76475517,which only exists in Caucasians with HLA-A23 or HLA-A24 alleles,and the atrophy of the right amygdala(P=0.010,Pc=0.085)at baseline.In particular,the haplotype(TGACAAGG),as a surrogate marker of HLA-A2,was founded to be positively associated with the atrophy of the right hippocampus(P=0.047)at baseline.Furthermore,we detected the above four associations in MCI sub-population analysis(rs9260168:P=0.002;rs3823342:P=0.002;rs76475517:P=0.009;TGACAAGG :P=0.005).(3)In hybrid population analysis,our study showed HLA-DRB1/DQB1 rs35445101,rs1130399,and rs28746809 were associated with the smaller baseline volume of left posterior cingulate(rs35445101:P=9.49×10-4,Pc=0.007;rs1130399 : P=0.001 Pc=0.011;rs28746809 : P=0.006,Pc=0.025;rs2854275: P=0.002,Pc=0.011)and rs2854275 was associated with the larger baseline volume of left posterior cingulate(P=0.002,Pc=0.011).Furthermore,we detected the above four associations in MCI sub-group analysis(rs35445101: P=0.021;rs1130399: P=0.008;rs28746809: P=0.029;rs2854275: P=0.020)and the above associations of two risk loci(rs35445101 and rs1130399)in NC sub-group analysis(rs35445101: P=0.014;rs1130399: P=0.033).With reference to the website http://hla.alleles.org,our study showed that left posterior cingulate was the pivotal region on which four loci target.The result of the three variants in HLA-DQB1 alleles tightly in one block and the fact that HLA-DQB1*03 allele and HLA-DQB1*02 allele cannot coexist in the same chromosome provide further evidence for that HLA-DRB1/DQB1 genetic variations target on the left posterior cingulate.CONCLUSION: Our study showed HLA-A2 was positively associated with theatrophy of the right hippocampus,four loci in HLA-DRB1/DQB1(rs35445101,rs1130399,rs2854275 and rs28746809)modulated the alteration of the left posterior cingulate,TNF-? SNPs at rs2534672 and rs2395488 were significantly positively associated with the volume of the left middle temporal lobe Our study suggested that HLA genetic variations were correlated with AD related brain structures on MRI in ADNI subjects,which started from the stage of NC or MCI.Our study provided preliminary evidences that HLA gene variants might participate in the structural alteration of AD associated brain regions,hence modulating the susceptibility of AD.Further research in large independent samples with diverse ethnicity is required to confirm the effects of HLA genes variants on AD.