The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients

Kelly A. Birdwell, Ben Grady, Leena Choi, Hua Xu, Aihua Bian, Josh C. Denny, Min Jiang, Gayle Vranic, Melissa Basford, James D. Cowan, Danielle M. Richardson, Melanie P. Robinson, Talat Alp Ikizler, Marylyn D. Ritchie, Charles Michael Stein, David W. Haas

Research output: Contribution to journalArticle

60 Citations (Scopus)

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. Conclusion: This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

Original languageEnglish (US)
Pages (from-to)32-42
Number of pages11
JournalPharmacogenetics and Genomics
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2012

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Electronic Health Records
Pharmacogenetics
Tacrolimus
Kidney
DNA
Cytochrome P-450 CYP3A
Pharmaceutical Preparations
Drug Monitoring
Linkage Disequilibrium
Immunosuppressive Agents
Transplant Recipients
Gold
Kidney Transplantation
Hemoglobins
Pharmacokinetics
Weights and Measures
Enzymes
Research
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Birdwell, Kelly A. ; Grady, Ben ; Choi, Leena ; Xu, Hua ; Bian, Aihua ; Denny, Josh C. ; Jiang, Min ; Vranic, Gayle ; Basford, Melissa ; Cowan, James D. ; Richardson, Danielle M. ; Robinson, Melanie P. ; Ikizler, Talat Alp ; Ritchie, Marylyn D. ; Stein, Charles Michael ; Haas, David W. / The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients. In: Pharmacogenetics and Genomics. 2012 ; Vol. 22, No. 1. pp. 32-42.
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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. Conclusion: This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.",
author = "Birdwell, {Kelly A.} and Ben Grady and Leena Choi and Hua Xu and Aihua Bian and Denny, {Josh C.} and Min Jiang and Gayle Vranic and Melissa Basford and Cowan, {James D.} and Richardson, {Danielle M.} and Robinson, {Melanie P.} and Ikizler, {Talat Alp} and Ritchie, {Marylyn D.} and Stein, {Charles Michael} and Haas, {David W.}",
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Birdwell, KA, Grady, B, Choi, L, Xu, H, Bian, A, Denny, JC, Jiang, M, Vranic, G, Basford, M, Cowan, JD, Richardson, DM, Robinson, MP, Ikizler, TA, Ritchie, MD, Stein, CM & Haas, DW 2012, 'The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients', Pharmacogenetics and Genomics, vol. 22, no. 1, pp. 32-42. https://doi.org/10.1097/FPC.0b013e32834e1641

The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients. / Birdwell, Kelly A.; Grady, Ben; Choi, Leena; Xu, Hua; Bian, Aihua; Denny, Josh C.; Jiang, Min; Vranic, Gayle; Basford, Melissa; Cowan, James D.; Richardson, Danielle M.; Robinson, Melanie P.; Ikizler, Talat Alp; Ritchie, Marylyn D.; Stein, Charles Michael; Haas, David W.

In: Pharmacogenetics and Genomics, Vol. 22, No. 1, 01.01.2012, p. 32-42.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients

AU - Birdwell, Kelly A.

AU - Grady, Ben

AU - Choi, Leena

AU - Xu, Hua

AU - Bian, Aihua

AU - Denny, Josh C.

AU - Jiang, Min

AU - Vranic, Gayle

AU - Basford, Melissa

AU - Cowan, James D.

AU - Richardson, Danielle M.

AU - Robinson, Melanie P.

AU - Ikizler, Talat Alp

AU - Ritchie, Marylyn D.

AU - Stein, Charles Michael

AU - Haas, David W.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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. Conclusion: This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

AB - 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. Conclusion: This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

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