title: The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.
abstract: OBJECTIVE
  Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.
  
  
  METHODS
  We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio.
  
  
  RESULTS
  In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates.
  
  
  CONCLUSIONS
  This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.
authors: Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennesse, USA.
authors: Kelly A
authors: KA
authors: Birdwell
authors: Ben
authors: B
authors: Grady
authors: Leena
authors: L
authors: Choi
authors: Hua
authors: H
authors: Xu
authors: Aihua
authors: A
authors: Bian
authors: Josh C
authors: JC
authors: Denny
authors: Min
authors: M
authors: Jiang
authors: Gayle
authors: G
authors: Vranic
authors: Melissa
authors: M
authors: Basford
authors: James D
authors: JD
authors: Cowan
authors: Danielle M
authors: DM
authors: Richardson
authors: Melanie P
authors: MP
authors: Robinson
authors: Talat Alp
authors: TA
authors: Ikizler
authors: Marylyn D
authors: MD
authors: Ritchie
authors: Charles Michael
authors: CM
authors: Stein
authors: David W
authors: DW
authors: Haas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000367:Age Factors; D001835:Body Weight / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D030561:Databases, Nucleic Acid; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D057286:Electronic Health Records; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000276:immunology*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006454:Hemoglobins; D007166:Immunosuppressive Agents; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus