title: FKBP5 genetic variation:  association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder.
abstract: OBJECTIVE
  FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder.
  
  
  METHODS
  We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies.
  
  
  RESULTS
  Genotype-phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio=0.49; P=0.003) and 6-week response in the STAR*D replication study (odds ratio=0.74; P=0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation.
  
  
  CONCLUSIONS
  This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients.
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Katarzyna A
authors: KA
authors: Ellsworth
authors: Irene
authors: I
authors: Moon
authors: Bruce W
authors: BW
authors: Eckloff
authors: Brooke L
authors: BL
authors: Fridley
authors: Gregory D
authors: GD
authors: Jenkins
authors: Anthony
authors: A
authors: Batzler
authors: Joanna M
authors: JM
authors: Biernacka
authors: Ryan
authors: R
authors: Abo
authors: Abra
authors: A
authors: Brisbin
authors: Yuan
authors: Y
authors: Ji
authors: Scott
authors: S
authors: Hebbring
authors: Eric D
authors: ED
authors: Wieben
authors: David A
authors: DA
authors: Mrazek
authors: Richard M
authors: RM
authors: Weinshilboum
authors: Liewei
authors: L
authors: Wang
mesh_terms: D002478:Cells, Cultured; D003865:Major Depressive Disorder / Q000188:drug therapy*; D024202:Electrophoretic Mobility Shift Assay; D014644:Genetic Variation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D016896:Treatment Outcome; D000099159:Tacrolimus Binding Protein 5
chemical_list: D017367:Selective Serotonin Reuptake Inhibitors; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5