| Objective:Depression is a common and harmful mental disease. It is urgent to explore the physiopathological mechanism and the biomarkers for diagnosis and treatment of depression. Until recently, more attentions are paid on the hypothesis of micro RNA epigenetic regulation. A large number of studies confirmed that mi RNAs plays an important role in the process of development and differentiation of neurons in the central nervous system. Previous work showed that mi RNAs played a critical role in the pathogenesis and anti-depressive treatment. In particular, mi R-34b/c has been implicated in MDD risk and neural plastic function. However, the peripheral blood of mi R-34b/c dysregulation can be used as biomarkers of MDD? It has not been investigated. Based on the above research background, we design the following experiment to verify the mi R-34b/c as a basis for the MDD biomarkers, and the possible biological mechanisms were discussed.Methods:1. Preliminary study Using case-control study design, the expression levels of mi R-34b–5p and mi R-34c–5p in peripheral blood leukocytes of 35 MDD patients and 35 healthy controls were detected. The patients were either first episode or no prior antidepressant treatment.2. Reconfirm(1) Expression level verification Using case-control and forward-looking tracking study design, the expression levels of mi R-34b–5p and mi R-34c–5p in peripheral blood leukocytes of 80 MDD patients and80 healthy controls were detected. The patients underwent antidepressant treatment for 8weeks. The associations between peripheral blood of mi R-34b/c expression and MDD were applied.(2) Genetic susceptibility verification Using case-control study design, we evaluated the effect of mi R-34b/c gene polymorphisms and MDD, using data from 600 Han Chinese patients with MDD and 400 healthy volunteers. Allelic, genotypic and haplotypic associations were analyzed using UNPHASED and SPSS software.3. Bioinformatics validation Constucting the network of mi R-34b/c target genes by bioinformatics technology, in order to explore the biological mechanism of mi R-34b/c and MDD.Results:1. Preliminary study The mi R-34b–5p and mi R-34c–5p expression in MDD patients were significantly higher than those in control subjects(Z=2.457, P=0.014; Z=2.001, P=0.045). The expressions of mi R-34b–5p and mi R-34c–5p were positive correlated with the score of HAMD-17(r=0.599, P=0.001; r=0.470, P=0.001). The expression level of mi R-34b–5p was significantly lower in patients with suicidal idea(Z=9.603, P=9.603). N1 and P2 latency of P300 were positive correlated with mi R-34c–5p(r=0.671, P=0.001;r=0.387,P=0.048).2. Reconfirm(1)Expression level verification(1) The expression of mi R-34c–5p in MDD patients was significantly higher than these in control subjects(t=2.015, P=0.046), and obviously decreased after treatment(t=3.213, P=0.002). No significant association was observed between mi R-34b–5p expression and MDD. The ROC curve analysis showed that the AUC area of mi R-34c–5p was 0.611 with 49.15% sensitivity and 75.00% specificity.(2) The expression of mi R-34c–5p was positive correlated with the score of HAMD-17(r=0.302, P=0.019), and the expression change after treatment with HAMD-17 points rate was positively correlated(r=0.281, P=0.035). (3) The expression level of mi R-34b–5p was significantly lower in patients with family history(t=-2.434, P=0.018), and higher in patients with suicidal idea(t=-2.186,P=0.033).(4) The expression of mi R-34c–5p was negatively correlated with verbal function(r=-0.320, P=0.032), delayed memory(r=-0.463, P=0.001) and the total number of color words(r=-0.329, P=0.026). The expression of mi R-34c–5p was positively correlated with attachment A time(r=0.375, P=0.012), and the attachment B time(r=0.477, P=0.001).(5) The expression of mi R-34c–5p was positively related with N1 latency(r=0.321,P=0.022). The expression of mi R-34b–5p was positively related with N1 and N2 latency(r=0.568, P=0.001; r=0.482, P=0.001).(2) Genetic susceptibility verification(1) No significant genotypic and allelic associations were observed in MDD even by gender and family history stratification.(2) After discarding data with severe negative life events in our stratified population,we found an association between rs4938723, rs2187473 polymorphisms and MDD in the dominant models(TC/CC vs. TT, OR=1.45, P=0.027; TC/CC vs. TT, OR=3.32, P=0.030).In haplotypic analysis, the C-G haplotype(rs4938723/rs28757623) showed the strongest association with MDD(OR=1.93, adjusted P=0.026).(3) The interactions between MDD and rs4938723 genotype were significant for the complete classification number(F=4.921, P=0.027), the number of response errors(F=3.943, P=0.047). The interactions between MDD and rs2187473 genotype were significant for immediate memory(F=4.320, P=0.038), the time for reading font-color(F=4.684, P=0.031) and time for eliminating the interference of word(F=3.890, P=0.049).The main effects of SNP rs28757623 locus in complete classification number(F=3.973, P=0.047), the number of correct responses(F=8.765, P=0.003), the number of response errors(F=7.479, P=0.006), the rate of conceptualization level(F=14.123, P=0.000) were significant.3. Bioinformatics validation The mi R-34b/c play an important role not only in tumor related pathways, but also in cell apoptosis, neural plasticity, and bacterial infection and cellular immunity. They can regulate Wnt signaling pathway the Notch signaling pathway, Cytokine- Cytokine receptor interaction and other important biological function.Conclusion:1. Our study found that aberrant expression of mi R-34c–5p in peripheral blood are associated with MDD. Mi R-34 c not only showed higher expression in patients with MDD,but also decreased after antidepressant treatment. The change of expression are associated with the severity of the depression, suicidal idea and cognitive function. The mi R-34 c expression levels of peripheral blood leukocytes may become an important biomarker for the diagnosis and treatment of MDD.2. The variants within Mi R-34b/c are associated with MDD in Han Chinese population after stratifying by negative life events and cognitive function.3. Bioinformatics analysis showed that mi R-34 b/c may participate in some signaling pathways associated with MDD, including apoptosis, neural plasticity, bacterial infection and immunity. |
PDF Full Text Request