MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder

Nielsen, Maria Gabriela; Congiu, Chiara; Bortolomasi, Marco; Bonvicini, Cristian; Bignotti, Stefano; Abate, Maria; Milanesi, Elena; Conca, Andreas; Cattane, Nadia; Tessari, Elisabetta; Gennarelli, Massimo; Minelli, Alessandra

doi:10.1016/j.jad.2015.05.003

Cited by 14 publications

(12 citation statements)

References 64 publications

(95 reference statements)

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“…Indeed, fibroblasts are maintained in cultures in a controlled, reproducible environment, and after several rounds of cell division they are minimally affected by confounding factors (for example, lifestyle or medication use) to which, in contrast, PBCs are exposed. 22 , 35 , 46 , 53 , 54 …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, GAPDH has been already used as a reference in MDD studies using fibroblasts and PBCs. 34 , 35 , 36 Therefore, the relative expression levels of the target genes in the patient groups were calculated according to the comparative Ct method ( −ΔΔCt method) 37 using GAPDH as the reference gene. Each determination was repeated in duplicate.…”

Section: Methodsmentioning

confidence: 99%

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Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

et al. 2015

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Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance–related processes may be involved in several phenotypes, including the TRD.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

et al. 2015

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“…To the best of our knowledge, only one study used HDF to assess the functionality of genetic polymorphisms. In this study, the Catechol-O-methyltranferase ( COMT) Val158Met genetic polymorphism and its potential effect on COMT functionality were investigated in HDF from MDD patients [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Mesdom

Colle

Lebigot

et al. 2020

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Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective: The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods: The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results: HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion: The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action.

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“…We excluded an article related to bipolar disorder, an article that failed to isolate depression patients’ MTHFR status, an article related to ophthalmology, five meta-analyses, and one review article. In total, six relevant articles were identified for this review and we summarize our findings in Table 1 [ 6 - 11 ].…”

Section: Reviewmentioning

confidence: 99%

“…Additionally, the TT genotype of C677T appears to have modest effect on the risk of MDD [ 10 , 13 , 17 ]. A recent study by Nielsen and co-workers on A1298C failed to find the same association between A1298C and MDD despite assessing a large population of 613 patients and 463 controls [ 6 ]. The study, however, additionally noted that the strong association was found only in female patients and controls with higher statistical power than the previous studies.…”

Section: Reviewmentioning

confidence: 99%

Methylenetetrahydrofolate Reductase A1298C Polymorphism and Major Depressive Disorder

Cho¹,

Amin

An³

et al. 2017

Cureus

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Major depressive disorder (MDD) is a disorder that carries significant psychosocial and economic implications. Research efforts have focused on identifying biomarkers that can aid in the prediction, diagnosis, and efficacious treatment of MDD. Most of this focus has been placed on a polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T. MTHFR C677T is screened during MDD diagnosis in many protocols. However, MTHFR C667T poses conflicting data in various ethnic groups and geographic populations calling into question its utility. Another polymorphism, MTHFR A1298C, has often taken the back-seat to MTHFR C677T in respect to research focus. MTHFR A1298C is implicated in irregular homocysteine metabolism and aberrant folate cycles and, through this, it may play a role as either a driver in the development of MDD or as a predictive or diagnostic marker, possibly in combination with C677T. The number of studies evaluating MTHFR A1298C and the power of those studies is lacking and thus larger studies are required to confirm the association between this polymorphism and MDD.

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MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder

Cited by 14 publications

References 64 publications

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Methylenetetrahydrofolate Reductase A1298C Polymorphism and Major Depressive Disorder

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