title: FAS -670A>G genetic polymorphism Is associated with Treatment Resistant Depression.
abstract: BACKGROUND
  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 therapeutic 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 -670A>G and FASL -844T>C functional polymorphisms never been evaluated in the context of depression and antidepressant therapy, we genotyped FAS -670A>G and FASL -844T>C 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 prognosis (relapse or TRD: OR=6.200; 95% CI: [1.875-20.499]; p=0.001), and we observed that patients carrying this allele have a higher risk to develop TRD (OR=10.895; 95% CI: [1.362-87.135]; p=0.008). Moreover, multivariate analysis adjusted to potentials confounders showed that patients carrying G allele have higher risk of early relapse (HR=3.827; 95% CI: [1.072-13.659]; p=0.039). FAS mRNA levels were down-regulated among G carriers, whose genotypes were more common in TRD patients. No association was found between FASL-844T>C genetic polymorphism and any treatment phenotypes.
  
  
  CONCLUSIONS
  Small sample size. Patients used antidepressants with different mechanisms of action.
  
  
  CONCLUSIONS
  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 -670A>G 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 neuroplasticity.
authors.affiliation: Molecular Oncology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, Porto, Portugal; Núcleo de Investigação e Informação em Farmácia-Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Technologies, Polytechnic Institute of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal. Electronic address: mmarlenes@gmail.com.
authors.forename: Marlene
authors.initials: M
authors.lastname: Santos
authors.affiliation: Hospital de Magalhães Lemos, Porto, Portugal; Instituto Superior de Ciências da Saúde, Norte, Portugal.
authors.forename: Serafim
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; Núcleo de Investigação e Informação em Farmácia-Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Technologies, Polytechnic Institute of Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Lima
authors.affiliation: Clínica Médico-Psiquiátrica da Ordem, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mota-Pereira
authors.affiliation: Trás-os-Montes e Alto Douro Hospital Centre, Vila Real, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Pimentel
authors.affiliation: Trás-os-Montes e Alto Douro Hospital Centre, Vila Real, Portugal.
authors.forename: Dulce
authors.initials: D
authors.lastname: Maia
authors.affiliation: Hospital de Magalhães Lemos, Porto, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Correia
authors.affiliation: Hospital de Magalhães Lemos, Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gomes
authors.affiliation: Núcleo de Investigação e Informação em Farmácia-Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Technologies, Polytechnic Institute of Porto, Porto, Portugal.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Cruz
authors.affiliation: Molecular Oncology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, Porto, Portugal; Department of Pathology and Molecular Immunology, ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal; Health Faculty of University Fernando Pessoa, CEBIMED, Porto, Portugal; Research Department, Portuguese League Against Cancer (Norte), Porto, Portugal. Electronic address: ruimedei@ipoporto.min-saude.pt.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000328:Adult; D000483:Alleles; D003865:Major Depressive Disorder / Q000235:genetics*; D061218:Depressive Disorder, Treatment-Resistant / Q000235:genetics*; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012306:Risk; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019014:fas Receptor
keywords: Antidepressants; FAS; Neurogenesis; Neuroplasticity; Polymorphisms; Treatment Resistant Depression