Document Detail


FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder.
MedLine Citation:
PMID:  23324805     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: 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.
CONCLUSION: 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:
Katarzyna A Ellsworth; Irene Moon; Bruce W Eckloff; Brooke L Fridley; Gregory D Jenkins; Anthony Batzler; Joanna M Biernacka; Ryan Abo; Abra Brisbin; Yuan Ji; Scott Hebbring; Eric D Wieben; David A Mrazek; Richard M Weinshilboum; Liewei Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  23     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-07-05     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  156-66     Citation Subset:  IM    
Affiliation:
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
Cells, Cultured
Depressive Disorder, Major / drug therapy*
Electrophoretic Mobility Shift Assay
Genetic Variation*
Humans
Mutagenesis, Site-Directed
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Serotonin Uptake Inhibitors / therapeutic use*
Tacrolimus Binding Proteins / genetics*
Treatment Outcome
Grant Support
ID/Acronym/Agency:
K22 CA130828/CA/NCI NIH HHS; K22 CA130828/CA/NCI NIH HHS; KL2 TR000136/TR/NCATS NIH HHS; KL2TR000136/TR/NCATS NIH HHS; P50 CA102701/CA/NCI NIH HHS; P50CA102701/CA/NCI NIH HHS; R01 CA132780/CA/NCI NIH HHS; R01 CA132780/CA/NCI NIH HHS; R01 CA138461/CA/NCI NIH HHS; R01 CA138461/CA/NCI NIH HHS; R01 GM028157/GM/NIGMS NIH HHS; R01 GM28157/GM/NIGMS NIH HHS; R21 GM086689/GM/NIGMS NIH HHS; R21 GM86689/GM/NIGMS NIH HHS; U01 GM061388/GM/NIGMS NIH HHS; U19 GM61388/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Serotonin Uptake Inhibitors; EC 5.2.1.-/Tacrolimus Binding Proteins; EC 5.2.1.8/tacrolimus binding protein 5
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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