SORL1 Rs11218343 Is Associated With Late-onset Alzheimer’s Disease: A Replication Study And Meta-analyses

Background Alzheimer’s disease(AD)is one of the neurodegenerative diseases,gradually appearing the progressive decline in cognitive function and behavior disorder.AD is the most common type of dementia.AD is histopathologically characterized by intracellular neurofibrillary tangles,extracellular neuritic plaques and the loss of neurons and synapses.The etiology and pathogenesis of AD are indeterminate,mainly determined by the combined effects of genetic and environmental factors.The genetic factors account for a higher proportion of the 80%.Concerning the etiology and pathogenesis of AD,there are multiple working hypotheses,of which the most extensive is the hypothesis of amyloid-β(Aβ)protein falls.This hypothesis supposes that the generation and elimination imbalance of Aβ is the initial event of neuronal degeneration and dementia.The related studies demonstrated that the expression level of the sortilin related receptor 1(SORL1)gene was lower in late-onset Alzheimer’s disease(LOAD)patients than normal controls.The main pathological mechanism is that SORL1 emerges as a central regulator of trafficking and processing of amyloid precursor protein(APP),which could defect the amyloidogenic processing of APP to Aβ.Recently,several large genome-wide association studies(GWAS)confirmed that SORL1 rs11218343 was significantly associated with LOAD risk in Caucasians.Objectives: To evaluate the influences of SORL1 gene on the risk of LOAD in the Han Chinese population.Methods: We performed a case-control study to explore the association in Northern Han Chinese population.We investigated 1358 healthy control subjects and 992 sporadic LOAD patients matched for age and gender.The rs11218343 and Apolipoprotein E(APOE)gene were genotyped using the improved multiplex ligase detection reaction(im LDR).The differences in allele and genotype between cases and controls were assessed using the chi-square test or Fisher’s exact.The associationbetween rs11218343 and LOAD was estimated with odds ratios(ORs)and 95%confidence intervals(CIs)by logistic regression model,adjusting for age of onset and gender.As the ethnic-specific susceptibility and sample volume exist,we meta-analyzed our data with those from previously related studies further for extra accuracy(28804 cases and 52954 controls included).Results: Our study showed significant difference between LOAD and controls in the genotypic frequency(P=0.028).Adjusting for age,gender and APOE ? 4 status,the logistic regression analysis showed the minor allele(C allele)in rs11218343 decreased the risk of LOAD in recessive(OR=0.641,95%CI=0.464–0.884,P=0.007)and additive model(OR=0.873,95%CI=0.765–0.996,P=0.043).Furthermore,the total sample was divided into APOE ε4 carriers and non-carriers.We only found protective association in APOE ε4 non-carriers in recessive model(OR=0.561,95%CI=0.386–0.815,P=0.002).Our meta-analysis showed that the C allele within rs11218343 played a protective role in LOAD risk in Caucasian subgroup(OR=0.77,95%CI=0.72–0.83),Asian subgroup(OR=0.85,95%CI=0.79–0.91)and the whole populations(OR=0.81,95%CI=0.76–0.85).Conclusions: Our study demonstrates that the minor allele(C allele)of SORL1rs11218343 shows a protective effect on LOAD risk in northern Han Chinese population.Furthermore,this conclusion was validated in different populations in our meta-analysis.