Association between miR-182 rs76481776 Polymorphism and Antidepressant Treatment Response in Patients with Depression.

INTRODUCTION

Major depressive disorder (MDD) is a prevalent affective disorder encountered in clinical practice [ 1 ]. It is primarily characterized by persistent low mood, impaired concentration, slowed cognitive processing, memory disturbances, and suicidal ideation, all of which significantly compromise patients’ quality of life [ 2 , 3 ]. Therefore, timely diagnosis and appropriate intervention are crucial [ 4 ]. MDD has emerged as a leading cause of disability worldwide and constitutes a substantial portion of the global disease burden [ 5 , 6 ]. Although antidepressant medications are the cornerstone of clinical treatment for depression, their remission rates are modest, and the risk of recurrence remains high [ 7 , 8 ]. Furthermore, there is substantial inter-individual variability in the therapeutic response to antidepressant medications [ 9 ]. Accumulating evidence suggests that genetic variations may partially account for individual differences in antidepressant treatment outcomes [ 10 , 11 ]. Hence, investigating the predictive value of specific gene polymorphisms about treatment response in MDD may offer a scientific foundation for advancing personalized and precise treatment strategies for depression.

MicroRNAs (miRNAs) regulate gene expression by targeting and binding to the 3’ untranslated region (3’UTR) of target gene mRNAs [ 12 ], and are involved in depression-related pathophysiological processes such as neuroplasticity, neurotrophism, stress responses, and treatment response [ 13 , 14 ]. Accumulating evidence indicates that certain miRNAs are abnormally expressed in patients with MDD, and their expression levels are closely correlated with the severity of depressive symptoms and the efficacy of antidepressant therapy [ 15 , 16 ]. miR-182 has been implicated in the regulation of drug resistance in multiple myeloma [ 17 ]. Furthermore, miR-182-5p has been linked to depression-like behaviors [ 18 ]; knockout of miR-182-5p can alleviate chronic social defeat stress (CSDS)-induced depression-like behaviors in mice and inhibit neurogenesis [ 19 ]. The single-nucleotide polymorphism (SNP) rs76481776 is located in the enhancer region of miR-182 [ 20 ] and has been significantly associated with primary open-angle glaucoma (POAG) [ 21 ]. In the Greek population, individuals carrying the T allele of rs76481776 exhibit an increased risk of developing POAG [ 22 ]. Moreover, this T allele may interfere with the processing of pre-miR-182, potentially contributing to circadian rhythm disturbances observed in MDD patients with insomnia-type metabolic disorders [ 23 ]. However, the potential role of the miR-182 rs76481776 polymorphism in modulating antidepressant treatment response in MDD remains to be elucidated. Meanwhile, research has demonstrated that reduced levels of BDNF in MDD patients are associated with a greater number of depressive episodes [ 24 ] and that antidepressants may exert therapeutic effects, at least in part, through upregulation of BDNF expression [ 25 ]. Database prediction results indicate that BDNF is a downstream target of miR-182. Therefore, we hypothesized that the T allele of miR-182 rs76481776 may enhance miR-182 expression through its potential enhancer activity, thereby suppressing the expression of the downstream target gene BDNF , impairing neuroplasticity, which could ultimately lead to the induction or exacerbation of depressive symptoms and reduce the therapeutic efficacy of antidepressants on neural function.

In this study, we explored the predictive value of the rs76481776 polymorphism for treatment response in depression by analyzing differences in genotype distribution between MDD and healthy controls, and by integrating clinical characteristics with long-term treatment follow-up data. This approach was expected to provide a new theoretical basis and practical insights for the precise treatment of depression.

METHODS

Study Participants

Sample size estimation was performed using G*Power 3.1 software. The effect size w was set to 0.3, α err prob = 0.05, power (1−β err prob) = 0.95, and Df = 5. The results indicated that a minimum of 220 participants was required. A total of 360 participants were ultimately included, ensuring sufficient statistical power to detect the hypothesized effect. 180 Patients diagnosed with MDD by the Hospital of Chengdu University of Traditional Chinese Medicine were enrolled in this study. The inclusion criteria: fulfillment of the diagnostic criteria for MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); an initial score of more than 24 on the 17-item Hamilton Depression Rating Scale (HAMD-17); age between 20 and 65 years; and being first-episode cases without prior exposure to pharmacological treatment, physical therapy, or structured psychological interventions. The exclusion criteria: comorbidity with severe somatic diseases; presence of other psychiatric disorders; systematic use of psychotropic medications or any antidepressants; history of electroconvulsive therapy or ongoing structured psychotherapy; and known hypersensitivity to study medications.

180 Healthy controls were recruited from the Physical Examination Center of our hospital during the same period. The control group was age-matched to the MDD patients and had no personal or family history of psychiatric disorders. All participants scored below 7 on HAMD-17.

This study was approved by the Ethics Committee of Hospital of Chengdu University of Traditional Chinese Medicine (IRB No. 2020056), and all subjects provided written informed consent. The entire research procedure was conducted following the ethical principles of the Declaration of Helsinki.

Efficacy Assessment

HAMD-17 was employed to quantitatively evaluate the severity of depressive symptoms. The evaluation was carried out by professionally trained physicians through structured interviews combined with clinical observations. The scoring system was defined as follows: a score of 0−7 indicated the absence of depressive symptoms, 8−17 indicated mild depression, 18−24 indicated moderate depression, and a score of ≥ 24 indicated severe depression.

All MDD patients received standardized antidepressant therapy. The treatment regimen included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs), with dosages individually adjusted based on clinical conditions. Treatment efficacy was assessed using the HAMD-17 at baseline (M0), one month after initiation of treatment (M1), six months (M6), and twelve months (M12) post-treatment initiation. Efficacy criteria included the total HAMD score and the percentage reduction in score. A post-treatment HAMD total score of ≤ 7 was considered indicative of clinical remission [ 26 ], while a reduction of ≥ 50% from baseline was defined as the threshold for clinical effectiveness [ 27 ].

Genotyping

A total of 5 ml of fasting venous blood was collected from each research subject in the early morning. One portion was transferred into EDTA anticoagulant tubes (BD Biosciences) and centrifuged at 3,000 rpm for 10 minutes at 4°C within 2 hours after collection to isolate plasma. The remaining portion was collected into serum separation tubes containing a gel separator (Hunan Sili Medical Technology Co., Ltd.) for serum isolation. All samples were stored at −80°C to prevent repeated freeze-thaw cycles, which may lead to nucleic acid degradation. DNA was extracted using the QIAamp DNA Blood Mini Kit (Qiagen), and the extracted DNA was stored at −20°C. The purity and concentration of the extracted DNA were assessed using a NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific). DNA samples that met the defined quality criteria (an A260/A280 ratio ranging from 1.8 to 2.0) were selected for further analysis. Genotyping was conducted using the TaqMan fluorescence quantitative polymerase chain reaction (PCR) method, and the resulting PCR data were analyzed with TaqMan Genotyping Software version 1.3.1. To validate the accuracy of the TaqMan probe detection results, 1.7% of the samples were randomly selected and subjected to DNA sequencing analysis.

RT-qPCR

Total RNA was extracted using the Trizol method and subsequently reverse-transcribed into cDNA using a miRNA reverse transcription kit (Qiagen). Using cDNA as a template, RT-qPCR amplification was carried out on a 7500HT PCR system (Applied Biosystems) with iTaq Universal SYBR Green Supermix (Bio-Rad). U6 and GAPDH were employed as the internal reference genes, and the relative expression was normalized and quantified using the 2 −DDCt method. All primers were commercially synthesized by Shanghai GenePharma Biotechnology Company. The primers employed for RT-qPCR were as follows: miR-182 forward: 5’-TGCGCTTTGGCAATGGTAGAACTC-3’, reverse: 5’-CCAGTGCAGGGTCCGAGGTATT-3’. BDNF forward: 5’-TCACACTCCACATCCCGTGAT-3’, reverse: 5’-TTACTCTGACCAACGCCCAAA-3’. U6 forward: 5’-GGGGACATCCGATAAAATTGG-3’, U6 reverse: 5’-ACCATTTCTCGATTTGTGCGT-3’. GADPH forward: 5’-GGTCGGAGTCAACGGATTTG-3’, reverse: 5’-TCAGCCTTGACGGTGCCATG-3’.

Furthermore, The cycle threshold difference (ΔCt) between the target gene and the reference gene for each sample was determined using the following formula: ΔCt = Ct value of the target gene − Ct value of the reference gene. Specifically, miR-182 was normalized to U6, and BDNF was normalized to GAPDH. Subsequently, the ΔCt difference between the experimental group and the control group (ΔΔCt) was calculated as follows: ΔΔCt = mean ΔCt of the experimental group − mean ΔCt of the control group. Finally, the relative expression of the target gene was determined using the formula 2 −DDCt , which reflected the fold change in gene expression in the experimental group relative to the control group.

Dual-luciferase Assay

The reporter gene vector (psiCHECK-2, Promega) was constructed to contain either the wild-type (WT) or mutant (MUT) sequence of the BDNF gene 3’UTR. This vector was then co-transfected with miR-182 mimic or miR-inhibitor into cells using Lipofectamine 2000 (Invitrogen). Forty-eight hours post-transfection, cells were harvested, and luciferase activity was measured to assess the regulatory effect of miR-182 on BDNF expression.

Statistical Analysis

Data analysis and graphical representation were conducted using SPSS 26.0 and GraphPad Prism 9. Data were assessed for normality using the Kolmogorov–Smirnov (K-S) test. To evaluate differences between the two groups, non-parametric tests were applied to non-normally distributed continuous variables, Student’s t tests were used for normally distributed continuous variables, and the chi-squared test was employed for categorical variables. To evaluate the representativeness of the sample population, the Hardy-Weinberg equilibrium (HWE) test was performed. The software employed to calculate the HWE was PLINK 1.9. The potential correlation between miR-182 expression and BDNF levels was examined using the Pearson correlation coefficient. In all statistical analyses, a p value < 0.05 was considered statistically significant.

RESULTS

Comparison of General Clinical Characteristics of Research Participants

A comparison of baseline clinical characteristics between 180 controls and 180 MDD patients revealed no statistically significant differences between the two groups in terms of age, sex, or smoking status ( p > 0.05). The baseline HAMD-17 score for patients in the MDD group was 35.01 ± 6.11. The primary antidepressant medications administered included SSRIs in 92 cases, SNRIs in 74 cases, and TCAs in 14 cases ( Table 1 ).

Distribution of miR-182 rs76481776 Genotypes in the MDD Group and the Control Group

At the genotypic level, codominant model analysis indicated that the CT and TT genotypes in the MDD group were potentially associated with an increased risk of developing MDD (CT genotype: p = 0.008, odds ratio [OR] = 1.979, 95% confidence interval [CI] = 1.189−3.293; TT genotype: p = 0.024, OR = 4.499, 95% CI = 1.227−16.496). Under the dominant model (CT + TT vs. CC), the frequency of individuals carrying the CT + TT genotype was significantly higher in the MDD group (33.89%) compared to the control group (18.89%) ( p = 0.001, OR = 2.201, 95% CI = 1.356−3.573). Similarly, in the recessive model (TT vs. CT + CC), the TT genotype was more prevalent in the MDD group (6.11%) than in the control group (1.67%) ( p = 0.029, OR = 3.840, 95% CI = 1.053−14.005). At the allelic level, carriage of the T allele was associated with a significantly increased risk of MDD ( p < 0.001, OR = 2.182, 95% CI = 1.424−3.345) ( Table 2 ).

Association of miR-182 Expression with MDD

The relative expression of miR-182 in the MDD patient group was significantly higher than that in the control group ( Fig. 1A ). miR-182 demonstrated strong diagnostic performance for MDD, with an area under the curve of 0.8975, a sensitivity of 70% and a specificity of 93.33% ( p < 0.0001) ( Fig. 1B ). Further analysis of miR-182 expression across different genotypes revealed that, in the control group, there was no significant difference in miR-182 expression between individuals with the CC genotype and those with the CT + TT genotypes. In contrast, within the MDD group, individuals carrying the CT + TT genotype exhibited significantly higher miR-182 expression ( p < 0.001) ( Fig. 1C ).

Comparison of General Clinical Information among Different Genotypes in Patients with MDD

General clinical data of 119 MDD patients with the miR-182 rs76481776 CC genotype and 61 MDD patients with the CT + TT genotype were compared. The results indicated no statistically significant differences between the two groups in terms of age, sex, smoking status, or types of antidepressant medications used (SSRI, SNRI, TCA). However, significant differences were observed in baseline HAMD scores and treatment outcomes after 12 months. The initial HAMD score was significantly higher in patients with the CT + TT genotype (39.19 ± 5.13) compared to those with the CC genotype (32.86 ± 5.44). With regard to treatment remission, defined as a HAMD score ≤ 7, 49 patients with the CC genotype achieved remission and 70 did not, whereas only 11 patients with the CT + TT genotype achieved remission and 50 did not. Patients carrying the CT + TT genotype not only exhibited more severe depressive symptoms at baseline but also demonstrated a lower remission rate following 12 months of treatment ( Table 3 ).

Evaluation of the Influence of Different Genotypes on the Efficacy of Antidepressant Drugs

This study compared the efficacy of antidepressant treatment between 119 MDD patients with the miR-182 rs76481776 CC genotype and 61 MDD patients with the CT + TT genotype. The results demonstrated that at three follow-up time points (M1, M6, and M12), the clinical effectiveness rate was consistently higher in patients with the CC genotype than in those with the CT + TT genotype. The CT + TT genotype of miR-182 rs76481776 may be associated with a reduced response to antidepressant treatment ( Table 4 ).

At M0, HAMD scores were comparable between the two genotype groups. However, as treatment progressed (M1→M6→M12), symptom improvement was more pronounced in CC genotype carriers, whereas patients with the CT + TT genotype exhibited less improvement and more severe long-term symptoms ( Fig. 2A ). At each time point (M1, M6, and M12), the HAMD score reduction rate was significantly greater in the CC genotype group than in the CT + TT genotype group ( p < 0.001). Moreover, the reduction rate in the CC group increased progressively over time, while the increase in the CT + TT group was relatively modest. The CT + TT genotype was associated with inferior antidepressant efficacy, and this therapeutic disadvantage was sustained throughout the treatment period ( Fig. 2B ).

Targeted Regulation of the BDNF Gene by miR-182 and the Association between the Two in MDD

miR-182 can directly target and bind to the 3’UTR of the BDNF gene, thereby negatively regulating its expression. When cells were transfected with the BDNF -WT vector, luciferase activity was significantly decreased in the miR-mimic group, whereas it was markedly increased in the miR-inhibitor group. In contrast, no significant differences in luciferase activity were observed among the groups when the BDNF -MUT vector was used ( Fig. 3A , 3B ). The expression of BDNF in the MDD group was significantly lower compared to that in the control group ( Fig. 3C ). Significant differences in BDNF expression were found between MDD patients and controls across genotypes: within the control group, no significant difference was observed between the CC genotype and the CT + TT genotype. However, in the MDD group, BDNF expression in individuals with the CT + TT genotype was significantly lower than those with the CC genotype ( Fig. 3D ). Furthermore, in clinical samples from MDD patients, miR-182 expression was significantly and negatively correlated with BDNF expression ( Fig. 3E ).

DISCUSSION

SNPs influence the metabolic efficiency of antidepressant drugs [ 28 ]. Research has demonstrated that the expression of miR-182-5p in small extracellular vesicles isolated from the plasma of patients with MDD is significantly elevated [ 29 ]. In this study, 180 MDD patients and 180 healthy controls were recruited, and we report, for the first time, that the miR-182 rs76481776 polymorphism was significantly associated with the risk of MDD onset and treatment response. Key findings include: the T allele and its corresponding CT/TT genotypes may confer an increased risk of developing MDD; among MDD patients, carriers of the CT + TT genotypes exhibited more severe baseline depressive symptoms, a lower remission rate, and a diminished long-term treatment response. Additionally, a potential molecular mechanism underlying this association has been identified. These findings may provide novel experimental insights into the genetic susceptibility to MDD and contribute to the advancement of personalized treatment strategies.

In terms of genetic association, the rs76481776 T allele was a significant risk factor for MDD. Patients carrying the T allele (CT/TT genotypes) exhibited higher baseline HAMD scores, a lower 12-month remission rate, and significantly reduced antidepressant efficacy—as indicated by a lower HAMD score reduction rate—at M1, M6, and M12 post-treatment compared to individuals with the CC genotype. These findings suggested that this genotype may be linked to greater initial symptom severity and diminished response to antidepressant treatment. Furthermore, the expression of miR-182 was significantly elevated in MDD patients compared to healthy controls, suggesting that its overexpression may contribute to the pathogenesis of MDD. Additional genotype-based analysis revealed that within the MDD group, patients with CT + TT genotypes had markedly higher miR-182 expression, indicating that this genetic variant may influence disease progression and antidepressant response through upregulation of miR-182. This observation aligns with previous studies showing that carriers of the rs76481776 T allele are more susceptible to insomnia symptoms [ 23 ]. Moreover, the increased expression of miR-182 in TT/CT genotypes implies a potential role in disease susceptibility through modulation of regulatory T cell function or immune regulatory pathways [ 30 ].

At the mechanistic level, this study demonstrated that miR-182 could specifically target BDNF and suppress its expression. The rs76481776 polymorphism may influence the transcription or stability of miR-182, with the T allele potentially leading to abnormally elevated levels of miR-182. This upregulation subsequently downregulates BDNF expression, which may impair neuroplasticity and contribute to more severe depressive symptoms and poorer efficacy of antidepressants [ 31 ]. This mechanism aligns with previous findings: miR-182 is reported to be upregulated in the peripheral blood of patients with schizophrenia and the hippocampus of animal models [ 32 ]. Furthermore, in a mouse model of CSDS, administration of a miR-182-5p agonist significantly prolonged immobility time and exacerbated impairments in neurogenesis [ 19 ]. Concurrently, T allele carriers may experience inhibition of the AKT/GSK3b signaling pathway, which blocks the transcriptional activation of BDNF and compromises the neuroplasticity repair processes induced by antidepressant treatment [ 19 ]. Additionally, existing research indicates that the effectiveness of antidepressant therapy is closely tied to the recovery of neurotrophic factors such as BDNF [ 33 , 34 ], and elevated miR-182 expression may hinder this recovery, leading to a diminished therapeutic response in individuals with the CT + TT genotypes.

Clinically, measuring the expression of miR-182 may aid in the diagnosis of MDD. Furthermore, in high-risk populations (e.g., individuals with a family history of MDD), analyzing the miR-182 rs76481776 genotype may help identify individuals with susceptibility genotypes such as CT + TT, enabling early preventive interventions. At the beginning of treatment, genotype testing may guide the development of more tailored therapeutic strategies for patients with the CT + TT genotype. However, this study has several limitations. First, it employed a single-center design with a relatively small sample size, and its geographical coverage was limited, excluding other regions in China and diverse ethnic populations. Consequently, the representativeness of the findings may be constrained. Future studies should adopt large-sample, multi-center designs to enhance the generalizability of the results. Second, potential selection bias may have influenced the findings. On one hand, all MDD patients were recruited from psychiatric outpatient clinics, which may have led to an overrepresentation of individuals with more severe symptoms or higher treatment-seeking motivation. On the other hand, the healthy control group was recruited from a hospital-based physical examination center, where participants may have had higher health awareness than the general population. These differences may have resulted in baseline imbalances between the two groups. This limitation could be mitigated in future studies by implementing community-based random sampling for control group recruitment. Additionally, the recruitment criteria imposed further constraints. MDD patients were restricted to those with a “first episode and no previous treatment,” potentially excluding individuals with recurrent episodes or those who had received psychological interventions. These excluded individuals may exhibit distinct gene expression profiles compared to first-episode patients. Meanwhile, the control group excluded individuals with a family history of mental illness, which may have resulted in excessive screening and increased genetic background differences between the two groups. These limitations may lead to either overestimation or underestimation of the association between rs76481776 and MDD risk or treatment response. To address these issues, future studies should consider relaxing the inclusion criteria—for example, by including recurrent MDD patients—adopting a “population matching” strategy to ensure strict alignment of demographic and geographic characteristics (such as age, sex, education level, and region) between groups, and expanding sample sources through multi-center collaboration. Stratified analyses based on geographical region and illness severity should also be conducted to further validate the observed associations. Moreover, this study focused solely on the regulatory effect of miR-182 on BDNF , without evaluating other potential target genes or their associated signaling pathways. Therefore, the complete molecular regulatory mechanisms of miR-182 in the onset and progression of depression remain unclear. Future research should systematically investigate other potential target genes and related signaling pathways of miR-182 to enhance the generalizability and reliability of the findings.

In conclusion, the miR-182 rs76481776 polymorphism was significantly associated with both the risk of depression onset and the response to antidepressant treatment. The CT and TT genotypes may serve as potential biomarkers for predicting initial symptom severity and poor treatment outcomes in MDD patients. These findings may contribute to the development of genotype-guided, individualized treatment strategies.

ACKNOWLEDGMENTS

We would like to thank Prof. Dr. Eser KILIC for his kind help and advice over the course of the present study.

Footnotes

Funding

None.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Ying Feng, Xiyao Jia. Data curation: Ying Feng, Lijie Yang. Formal analysis: Xiyao Jia, Ping Dai. Investigation: Haiyan Bi, Lijie Yang. Methodology: Haiyan Bi, Xiyao Jia. Project administration: Yanjie Tang. Resources: Haiyan Bi. Software: Lijie Yang, Ping Dai. Supervision: Yanjie Tang. Validation: Ying Feng, Ping Dai. Visualization: Ying Feng, Xiyao Jia, Yanjie Tang. Writing—original draft: Ying Feng, Xiyao Jia. Writing—review & editing: Yanjie Tang.

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