Genetic Association Between Apolipoprotein E, Apolipoprotein A1 And Apolipoprotein A4 Gene Polymorphisms And Schizophrenia

Objects:Schizophrenia?SZ?is a complex multidimensional disease caused by environmental and genetic factors.Studies have shown that lipid metabolism is closely related to monoamine neurotransmitters,which is closely related to the pathophysiology of schizophrenia.The aims of this study were to investigate the relationship between apolipoprotein E?APOE?,apolipoprotein A1?APOA1?and apolipoprotein A4?APOA4?gene polymorphisms and SZ in Chinese Han population from the perspective of population genetics,and to provide evidence for exploring the possible molecular mechanisms of SZ and to find molecular targets for antipsychotic drugs.Methods:Using case-control study,2680 SZ cases diagnosed by two clinicians in Huai'an Third People's Hospital from 2009 to 2018 were included in the case group.2223 healthy controls?1365 males and 858 females?excluded family history of psychosis were included in the study.Target Single Nucleotide Polymorphisms?SNPs?were selected by combining linkage disequilibrium analysis with bioinformatics function prediction.TaqMan genotyping was used to detect the four SNPs variation of APOE?rs769450,rs405509,rs7412,rs429358?,rs5072 variation of APOA1 and rs1268354 variation of APOA4.The Association of APOE,APOA1 and APOA4 gene polymorphisms with SZ were analyzed by logistic regression analysis.The association were estimated by Odds Ratio,?OR?and 95%confidence interval?95%CI?,and then stratified by gender.61 first diagnosed SZ cases,64 SZ cases in convalescence period and 84 healthy controls participated in community physical examination were collected from the Third People's Hospital of Huai'an City.The levels of APOE,APOA1 and APOA4 messenger RNA?mRNA?in peripheral blood mononuclear cells were determined by real-time polymerase chain reaction.Triglyceride?TG?levels were determined by Enzymatic,levels APOA1 levels were determined by turbidimetric immunoassay and high-density lipoprotein cholesterol?HDL-C?levels were determined by homogeneous method.The levels of total transcripts,different variant transcripts of APOE,APOA1,APOA4 as well as TG,ApoA1 and HDL-C protein did not obey Gaussian distribution.The levels of gene expression and the levels of TG,ApoA1 and HDL-C protein in cases and controls and among different genotypes were analyzed by Mann�Whitney U nonparametric test or K-sample nonparametric test.Results:The allele distributions of 6 loci in the controls conformed to Hardy-Weinberg equilibrium?HWE??P>0.05?.The results of association analysis showed that the variations of rs769450,rs405509,rs5072 and rs1268354 polymorphisms of APOE gene,APOA1 gene and APOA4 gene were associated with SZ.After adjusting for age and gender covariates,the ORs?95%CIs?of rs769450,rs405509,rs5072 and rs1268354were1.121?1.006-1.250?,1.105?1.004-1.217?,0.822?0.749-0.901?and 1.123?1.027-1.228?,respectively,with P values of 0.039,0.042,3.220�10^-5 and 0.011.The ORs?95%CIs?in dominant models of rs5072 was 0.770?0.681-0.872?and the P value was 3.640�10^-5.The ORs?95%CIs?in recessive models of rs1268354 was 1.340?1.128-1.592?and the P value was 0.001.After Bonferroni correction,the association between rs5072 dominant model and rs1268354 recessive model with SZ was still statistically significant?P�6?.The results of gender stratification analysis showed that in female,rs769450,rs405509 of APOE and rs1268354 of APOA4 gene were associated with SZ.After adjusting for age covariates,the additive models ORs?95%CIs?were1.240?1.059-1.451?,1.208?1.049-1.390?and 1.262?1.109-1.436?,P values were 0.007,0.008 and 4.300�10^-5,respectively.Rs5072 was the significantly associated with SZ and consistent between men and women.The expression of APOA1 and APOA1transcript variant 4 in PBMCs of first episode SZ and the levels of APOA1 and HDL-C in serum were significantly lower than those in healthy control group?P<0.001?.The expression level of APOA1 transcript variant 4 significantly increased with the variation of rs5072 genotypes in the first episode SZ.The median?quartile?of AA genotype vs.AG genotype vs.GG genotype(2^-??CT)was 0.605?0.360,0.970?vs.0.774?0.337,1.378?vs.1.506?0.785,2.332?(P_trend=0.017),respectively.In females,the levels of APOE transcript variant 4 in PBMCs of patients with first episode SZ was significantly lower than that of healthy controls[0.886?0.594,1.596?vs.1.641?0.808,2.891?,P=0.010].In males who were convalescent SZ patients,the expression levels of APOE mRNA in TT and TG genotypes at rs405509 were[0.703?0.188,0.976?]and[1.382?0.895,2.134?],respectively,P value was 0.023.In the females who were healthy controls,APOE expression levels in TT and TG genotypes were[1.072?0.548,1.919?]and[0.993?0.603,3.221?],P was 0.047.After receiving antipsychotic drugs for an average of?27.500�9.900?days,the serum triglycerides?TG?levels also showed significant increase[0.840?0.650,1.220?vs1.340?0.990,1.875?mmol/L,P value less than 0.001].The serum APOA1 levels increased[1.035?1.000,1.200?vs 1.080?1.000,1.220?g/L],with P value of 0.044.Conclusions:Our findings suggest that APOE genetic variations is involved in the the pathogenesis of SZ by regulating APOE gene expression and TG levels and it is necessary to control lipids for female SZ patients carrying mutative alleles of APOE.The variations in APOA1 and APOA4 significantly affect genetic susceptibility to SZ by down-regulating the expression of PBMCs.APOA1 gene transcripts and ApoA1 would be important molecular targets for antipsychotic drugs and the prognosis of SZ.