| ObjectiveSchizophrenia is a set of severe psychiatric disorders with lifetime prevalence of 4% worldwide. Schizophrenia is a chronic disease with high recurrence rate, high disability rate which makes the disease burden of schizophrenia is relatively high. According to the World Health Organization (WHO), the burden of mental illness will be 1/4 of the total disease burden by 2020. It is often accompanied by disordered perception, thinking, emotion, behaviour and other aspects of disorders and many uncoordinated mental activities. Schizophrenia includes both positive symptoms such as hallucination and delusion and negative symptoms such as social withdrawal and emotionlessness. In addition to positive symptoms and negative symptoms, cognitive impairment is also one of the core symptoms of schizophrenia patients.The etiology of schizophrenia remains unknown and the 5-serotonin receptor (HTR) hypothesis is one of the important hypotheses about the etiology of schizophrenia. HT3A and HT3B are all located on the chromosome llq23, the combination of the two units very similar to those observed in certain native 5-HT3 receptors. At present, there is no study on HTR3A3B polymorphism of the Han population with Schizophrania. Here,we aim to discuss the association of HTR3A andHTR3B receptors polymorphism with schizophrenia and clinical phenotype.MethodsThis case-control study involved patients with schizophrenia and healthy controls who met the inclusion criteria of the study. Peripheral blood sample (5 mL) was collected from all samples in the fasting state at 630 a.m. The blood sample was kept at -70℃ in the refrigerator. The single-nucleotide polymorphism (SNP) were selected according to the gene sequence of HTR3A and HTR3B confirmed by the National Center for Biotechnology Information database, or the SNPs with clinical significance as shown in previous studies.The allele frequency of the SNPs needed to be more than 10%. Based on the aforementioned criteria,21 SNP sites were selected. The Sequenom Mass Array (Sequenom, Inc.) platform was used for polymerase chain reaction (PCR) amplification and gene typing. At the same time,Positive and Negative Syndrome Scale(PANSS) was used to assess the patients features and the severity of clinical symptoms. MATRICS consensus cognitive battery(MCCB) was used to assess cognitive function of all the subjects.The result of the gene typing was imported to the Plink1.07 software for data analysis. All data of SNPs were imported to test the Hardy-Weinberg (H-W) equilibrium and minimum allele frequency (MAF) with the chi-square test. Then, the difference between the two groups of allele was compared with the Pearson chi-square test or the Fisher’s exact test. The difference in general information, such as age, gender, and education level, was evaluated between the two groups, with the t test or x2 test using the SPSS 20.0 software. One-factor analysis of variance (one-way ANOVA) was used to compare the PANSS scores in the SNPs or the overall score in the case group, and the least-significant difference assay was performed for the multi-comparison of the PANSS scores and the MCCB scores among different genotypes. The t test was used to compare the scores between homozygous A2A2 genotype and genotype with A1 allele.Results1. General information and gene typingThis study involved 139 patients with schizophrenia and 101 healthy controls. There was no significant difference in age, sex, marital status, or educational level between the two groups. All the SNPs in the two groups did not deviate from the H-W equilibrium (p=0.0513-1). The minimum allele frequency of the two groups was greater than 0.05 (MAF>0.05).2. Association of HTR3 A gene polymorphism with schizophrenia and the subtypesThere were significant differences between case group and control group in frequencies of allele of rs10789980、rs11604247、rs1176719(p=0.02,0.009,0.026),and the OR values were 1.558,2.124 and 1.646, while the lower limit of the confidence interval (L95) was 1.070,1.194,1.059 respectively. Hierarchical comparison results were found that there were significant differences between schizophrenia with negative symptoms and control group in frequencies of allele of rs10789980, rs11604247, rs1176719, rs10160548, rs1176713 (p=0.001,0.003,0.019,0.014,0.010),and the OR values were 2.172,2.594,1.845,1.772and1.876, while L95 were 1.381,1.333,1.101,1.118 and 1.125.3. Association of HTR3 B gene polymorphism with schizophrenia and the subtypesThere were significant differences between case group and control group in frequencies of allele of rs1176746、rs3782025、rs1672717 (P=0.031,0.049,0.046),and the OR values were 10.656,0.683 and 0.682, while the L95 was 0.963,0.999 and 0.993r espectively. Hierarchical comparison results were found that there were significant differences between schizophrenia with negative symptoms and control group in frequencies of allele of rs1176744、rs12795805 (p= rs1176744,rs12795805),and the OR values were 1.963,2.048, while L95 were 1.112、1.155.4. LD and haplotype analysisMajority of the SNPs in HTR3A and HTR3B were strong linkage disequilibrium. There were two haplotypes (block 1 and block 2) in all samples. The block2 was composed by rs1176722, rs2276302, rs1176719, rs10160548, rs1176713 and rs1182457.There were significant differences between case group and control group in frequencies of GAAGCC haplotypes (x2=8.600, p=0.003) and GAGGCC haplotypes (x2=4.390, p=0.036). There were three haplotypes in schizophrenia with positive symptoms. But there was no significant difference between the groups. There were three haplotypes in schizophrenia with negative symptoms.But there was no significant difference between the groups. The block2 was composed by rs12421126, rs1176746, rs176744, rs2276305, rs3782025 and rs1672717. There were significant differences between schizophrenia with negative symptoms and control group in frequencies of TCGGTT haplotypes (x2=4.461,p=0.035). The block3 was composed by rs1176722, rs2276302, rs1176719, rs10160548, rs1176713 and rs1182457.There were significant differences between schizophrenia with negative symptoms and control group in frequencies of GAGTTC haplotypes (x2=14.456, p=0.0001)5. Association of HTR3 A gene polymorphism with clinical phenotypeThere was significant difference in the PANSS negative symptom score among different genotypes of rs10789980 (F=5.574, p= 0.005). The intergroup comparison showed that the PANSS positive symptom score of the GG genotype was higher than that of the AA genotype (p=0.025), the PANSS negative symptom scores of the GG and GA genotypes were higher than that of the AA genotype, and the difference was very prominent (p= 0.004). There was a significant difference between genotypes of A1 allele carriers vs the homozygous A2A2 genotypes in the PANSS negative symptom score (t=3.237,p=0.001) There was no significant difference in the MCCB score among different genotypes of rs10789980. There were significant differences in the PANSS scores among different genotypes of rs1062613, rs1182457, rs1176722 and rs2276302, but no significant differences between the genotypes of A1 allele carriers and the homozygous A2A2 genotypes. In rs1176719 the PANSS scores of the AA genotype was higher than AG genotype (p=0.05). In rs10160548 the PANSS scores of the GG genotype was higher than TG genotype (P=0.016),and the PANSS negative symptom scores of the GG genotype was higher than TT genotype(p=0.033). The Connection Test (p=0.009、0.021、0.008、0.032) and the Digital Sequence (p=0.001、0.004.0.004、0.014) scores of the homozygous A2A2 genotypes were higher than the genotypes of A1 allele carriers of rs1062613, rs1176722, rs2276302 and rs1182457.6. Association of HTR3B gene polymorphism with clinical phenotypeThere were significant difference in the PANSS negative symptom scores among different genotypes of rsl 176744 (F=3.950,p=0.022) and rs3758987 (F=3.881, p=0.023). The intergroup comparison showed that the PANSS negative symptom scores of the A1A2 genotype was higher than that of the A2A2 genotype in analyzing rs1176744, rs3758987 and rs12795805. The PANSS negative symptom scores of the genotypes of A1 allele carriers were higher than the homozygous A2A2 genotypes of rsl 176744, rs3758987 and rs12795805. There were significant differences in the MCCB scores among different genotypes of HTR3B gene.Conclusions:1.HTR3A gene rs10789980,rs11604247 and rs1176719 polymorphisms might be associated with schizophrenia. The rs10789980,rs11604247,rs1176719,rs10160548 and rs1176713 polymorphisms might be associated with schizophrenia with negative symptoms.2. The rs10789980 polymorphism might influence the symptoms of schizophrenia with different effects on different symptoms. The rs10160548, rs2276302, rs1062613, rs1182457 and rs1176722 polymorphisms might be associated with the severity of schizophrenia. The rs10160548 polymorphism might influence the negative symptoms of schizophrenia. The rs1062613 polymorphism might influence the positive symptoms of schizophrenia.3. The rs10160548, rs1062613, rs1176722, rs2276302, rs1182457,rs1176719 and rs11604247 polymorphisms might be associated with cognitive impairment of schizophrenia.4. HTR3B gene rs1176746,rs3782025 and rs1672717 polymorphisms might be associated with schizophrenia. The rs1176744 and rs127958056 polymorphisms might be associated with schizophrenia with negative symptoms.5. HTR3B gene rs3758987,rs1176744 and rs12795805 polymorphisms might be associated with the negative symptoms of schizophrenia.6. No association was found between HTR3B gene polymorphism and cognitive function of schizophrenia. |
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