TREM2 Variants And Neurodegenerative Diseases: A Systematic Review And Meta-Analysis

Background: TREM2(triggering receptor expressed on myeloid cells 2)is a transmembrane glycoprotein.TREM2 gene located on chromosome 6p21.1 encodes the transmembrane receptor,which is mainly expressed in microglia,dendritic cells,osteoclasts,monocytes,granulocytes and macrophages.Recent studies have shown that TREM2 mainly regulates the endocytosis of microglia to apoptotic cells and inhibits inflammation in the brain.The mutation of the pathogenic TREM2 gene results in the loss of some functions of TREM2 protein and alters the behavior of microglia,including their response to amyloid plaques.TREM2 genetic polymorphism rs75932628 increased the risk of Alzheimer's disease(AD)in case-control studies.The correlation between TREM2 and AD further demonstrates that immune and inflammatory pathways are the cause of the disease,not the consequence of the disease.And other studies revealed rs75932628 variant conferred potential susceptibility to neurodegenerative diseases,such as frontotemporal dementia(FTD),Parkinson's disease(PD).TREM2 variants were reported to increase the risk of AD and even other neurodegenerative diseases(FTD,PD and amyotrophic lateral sclerosis(ALS)),but so far no definite conclusion has been drawn.To investigate the associations between rare variants in TREM2 and neurodegenerative diseases,the systematic review and meta-analysis were carried out.This study may shed new light on the diagnosis and treatment of diseases.Methods: PubMed,Medline,Embase and Chorane databases have been retrieved.This meta-analysis chose studies meeting the following criteria:(1)design: population-based case-control studies;(2)studies to explore potential associations between TREM2 and neurodegenerative diseases;(3)“odds ratio” and “95% confidence interval” were directly available,or sufficient genotype and allele data were presented for calculating OR and95 % CI.Additionally,published articles which reported genetic and phenotypic data on cases of homozygous TREM2 mutations were included in the study.The following contents were extracted from each selected study:(1)name of first author,(2)publication year,(3)ethnicity or country of origin,(4)number of cases and controls,(5)allelic counts in case and control groups,(6)OR and 95% CI.And we extracted genetic and phenotypic data of patients who carry homozygous TREM2 mutations in case reports.Odds ratio(OR)and 95 % confidence interval(95 % CI)were extracted from case-control studies to estimate the associations between TREM2 variants and neurodegenerative diseases(AD,frontotemporal dementia(FTD),Parkinson's disease(PD)and amyotrophic lateral sclerosis(ALS)).OR and 95% CI were extracted from case-control studies.The data were analyzed by R software to assess the relationship between TREM2 polymorphism and neurodegenerative disease.Fixed effect model was used to pool results in the analysis.Heterogeneity among different studies was evaluated by Cochran's Q statistic and I2 statistic.Funnel plots were used to evaluate the potential publication bias,which was also checked by Egger's linear regression analysis and Begg's rank correlation test.P value of the rank correlation test for each variant of TREM2 was greater than 0.05,indicating there was no statistically significant publication bias.And the genetic and phenotypic of published PLOSL case report with TREM2 mutations were collected.Results: A total of 39 papers(including 26 case-control studies and 13 case reports)were retrieved from these data base in this study.Three variants in TREM2(rs75932628(R47H),rs2234255(H157Y),and rs143332484(R62H))were significantly associated with AD risk,but the similar associations between rs104894002(Q33X),rs2234256(L211P),rs2234253(T96K),rs142232675(D87N)and AD were not proven(OR=3.71(95%CI: 0.83-16.52);OR=1.19(95%CI: 0.99-1.42,I2=46%);OR=1.58(95%CI:0.57-4.39);OR=1.72(95%CI: 0.66-4.52)).When we ignored the difference among races,we found a clear association of rs75932628 with AD susceptibility(OR=2.71,95%CI:2.39-3.09,I2=0%).Taking race into account,a more remarkable connection between the single nucleotide polymorphism(SNP)and AD could be found in Caucasians(OR=2.72,95%CI: 2.39-3.10,I2=0%).Nevertheless,the result couldn't be repeated in Asians(OR=1.83,95%CI: 0.36-9.31,I2=39%).Persuasive statistical evidence supported that rs2234255 has a significant association with AD(OR=3.00,95%CI: 1.34-6.68,I2=0%).But no significant association has been found in the subgroup analysis stratified by race(Asian and Caucasian subgroups)(Asian: OR=2.60,95%CI: 0.97-6.96,I2=16%;Caucasian: OR=3.96,95%CI: 0.99-15.82,I2=0%).Rs143332484 was affirmed as a susceptibility factor for AD once again(OR=1.62,95%CI: 1.45-1.80,I2=39%).Rs75932628 also increased risk of PD in North Americans and FTD,but not PD in Europeans or ALS.An association between rs75932628 of TREM2 polymorphisms and FTD susceptibility was corroborated(OR=2.24,95%CI: 1.20-4.17,I2=24%)after further investigations of 6 relevant citations.No significant association was detected(OR =0.36,95% CI: 0.97–1.91,I2=23%)between rs75932628 in TREM2 and PD when meta-analyses were conducted across nine independent studies.Then the PD series were divided into two subgroups,the North American subgroup and the European subgroup.The outcome showed that there was significant association between rs75932628 and PD risk in North Americans(OR =3.59,95% CI: 1.33–9.70,I2=0%).However the relation between the SNP and Europeans was not statistically significant(OR =1.20,95% CI: 0.83–1.72,I2=0%).Meta-analyses across all seven independent ALS datasets did not provide forceful statistical confirmation of rs75932628's effect on ALS susceptibility(OR=1.27,95%CI:0.77-2.11,I2=45%).In the systematic review,12 biallelic TREM2 mutations(e.g.rs104894002,rs201258663(T66M)and rs386834144,etc.)have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy(PLOSL)in 14 families.And homozygous mutations also have been reported to cause frontotemporal dementia without typical bone phenotypes in 7 families.Conclusion: In summary,our study offers systematic and high-quality evidence that TREM2 rs75932628 is a genetic risk factor for AD,FTD and North American PD.TREM2 rs2234255 and rs143332484 promote the process of AD and multiple variants in TREM2 show strong heritability in PLOSL.The verification of predisposing genes in neurodegenerative diseases can help reveal the pathogenesis of neurodegenerative diseases at the molecular level,which casts light on early prediction and therapeutic target.Given the ethnic and genetic differences,large-scale case-control studies on the associations between TREM2 polymorphisms and neurodegenerative diseases in different ethnicities and regions await further investigation.