FAS -670A>G genetic polymorphism Is associated with Treatment Resistant Depression

Abstract

a b s t r a c tBackground: Hippocampal neurogenesis has been suggested as a downstream event of antidepressants (AD) mechanism of action and might explain the lag time between AD administration and the ther-apeutic effect. Despite the widespread use of AD in the context of Major Depressive Disorder (MDD) there are no reliable biomarkers of treatment response phenotypes, and a significant proportion of patients display Treatment Resistant Depression (TRD). Fas/FasL system is one of the best-known death-receptor mediated cell signaling systems and is recognized to regulate cell proliferation and tumor cell growth. Recently this pathway has been described to be involved in neurogenesis and neuroplasticity. Methods: Since FAS -670A4G and FASL -844T4C functional polymorphisms never been evaluated in the context of depression and antidepressant therapy, we genotyped FAS -670A 4G and FASL -844T4C in a subset of 80 MDD patients to evaluate their role in antidepressant treatment response phenotypes. Results: We found that the presence of FAS -670G allele was associated with antidepressant bad prog-nosis (relapse or TRD: OR ¼6.200; 95% CI: [1. .499]; p¼0.001), and we observed that patients carrying this allele have a higher risk to develop TRD (OR ¼10.895; 95% CI: [1.362-87.135]; p¼0.008). Moreover, multivariate analysis adjusted to potentials confounders showed that patients carrying G allele have higher risk of early relapse (HR ¼3.827; 95% CI: [1.072-13.659]; p¼0.039). FAS mRNA levels were down-regulated among G carriers, whose genotypes were more common in TRD patients. No association was found between FASL-844T 4C genetic polymorphism and any treatment phenotypes. Limitations: Small sample size. Patients used antidepressants with different mechanisms of action. Conclusion: To the best of our knowledge this is the first study to evaluate the role of FAS functional polymorphism in the outcome of antidepressant therapy. This preliminary report associates FAS -670A4G genetic polymorphism with Treatment Resistant Depression and with time to relapse. The current results may possibly be given to the recent recognized role of Fas in neurogenesis and/or neu-roplasticity.

The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives

“…Among other genes involved in the modulation of neurogenesis and neuroplasticity, it is worth mentioning preliminary results reported for growth-associated protein 43 and the Fas/FasL system (Fabbri et al, 2015; Santos et al, 2015). growth-associated protein 43 codes for a neuron-specific cytosolic protein involved in the development of neuronal growth cones and axonal regeneration (Leu et al, 2010).…”

“…growth-associated protein 43 codes for a neuron-specific cytosolic protein involved in the development of neuronal growth cones and axonal regeneration (Leu et al, 2010). The Fas/FasL system is one of the best-known death-receptor mediated cell signaling systems, and it may be relevant to neurogenesis and neuroplasticity (Santos et al, 2015).…”

Identification and replication of RNA-Seq gene network modules associated with depression severity

“…FOXP3 also plays an essential role in maintaining homeostasis of the immune system, one of the pathways that have significant association with aggregate psychiatric disorders 40 . Variation in FAS, a gene involved in T cell activation and apoptosis, is associated with antidepressant prognosis 48 . A significant increase in FAS expression is also observed in depressed patients 49 .…”

IL6-174G > Cgenetic polymorphism influences antidepressant treatment outcome

“…For the analysis of the effect of IL6 and IL6R single nucleotide polymorphism (SNPs) in AD treatment response phenotypes, a cohort of 80 MDD patients was recruited at Hospital Magalhães Lemos, Oporto, Portugal, and followed for 27 months (14,15). MDD diagnosis was accomplished with Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the severity of the depressive symptoms with Beck Inventory Depression (BDI).…”

“…The evaluated AD treatment response phenotypes were: TRD, relapse, time to remission, and time to relapse. Clinical and sociodemographic characteristics of the patients were described elsewhere (14). The study was approved by the ethical committee of Hospital Magalhães Lemos and written informed consent according to 'The Code of Ethics of the World Medical Association' (Declaration of Helsinki) was obtained from each individual after explanation of the study.…”