NR1I2 Polymorphisms Are Related to Tacrolimus Dose-Adjusted Exposure and BK Viremia in Adult Kidney Transplantation Katherine A. Barraclough, 1,5 Nicole M. Isbel, 1 Katie J. Lee, 2 Troels K. Bergmann, 2 David W. Johnson, 1 Brett C. McWhinney, 3 Jacobus P. J. Ungerer, 3 Scott B. Campbell, 1 Diana R. Leary, 1 Seweryn Bialasiewicz, 4 Rebecca J. Rockett, 4 and Christine E. Staatz 2 Background. Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body. Aim. The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients. Methods. Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies. Results. In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was signifi- cantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) KgIh/L/mg versus 15 (9, 24) KgIh/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33Y7.73]; P=0.006). No significant difference in geo- metric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure. Conclusions. These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmaco- kinetics. Association of the 8055T allele with BK viremia suggests clinically significant ‘‘overimmunosuppression’’ in individuals with this genotype. Keywords: Haplotypes, Immunosuppression, Kidney transplantation, Pharmacogenetics, Single nucleotide polymorphisms. (Transplantation 2012;94: 1025Y1032) CLINICAL AND TRANSLATIONAL RESEARCH Transplantation & Volume 94, Number 10, November 27, 2012 www.transplantjournal.com 1025 K. Barraclough is currently supported by a National Health and Medical Research Council (NHMRC) Medical/Dental Postgraduate Research Scholarship. C. Staatz is currently supported by a Lions Medical Research Fellowship. D.Johnson is currently supported by a Queensland Gov- ernment Health Research Fellowship. This research is supported by a NHMRC Project Grant, number 511109, and an Amgen-Transplantation Society of Australia and New Zealand Research Grant. K.B. has received a research grant from Roche Pharmaceuticals. N.I. has received honoraria, travel sponsorships, research grants, and consul- tancy fees from Amgen, Roche, Astellas, Pfizer, Merck Sharp & Dohme, and Bristol-Myers Squibb. D.J. has received speakers’ honoraria, travel sponsorships, research grants, and consultancy fees from Janssen-Cilag, Amgen, Pfizer, and Roche. S.C. has been on Advisory Boards for Janssen-Cilag, Roche, Novartis, and Wyeth. C.S. has received a research grant from Roche Pharmaceuticals. The remaining authors declare no conflicts of interest. 1 Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia. 2 School of Pharmacy, University of Queensland, St Lucia, Brisbane, Australia. 3 Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia. 4 Sir Albert Sakzewski Virus Research Centre, Royal Brisbane and Women’s Hospital, Brisbane, Australia. 5 Address correspondence to: Katherine A. Barraclough, M.B.B.S.(Hons)., F.R.A.C.P., Department of Nephrology, Princess Alexandra Hospital Ipswich Road, Woolloongabba, Brisbane Qld 4102, Australia. E-mail: arbieb@hotmail.com K.B. participated in research design, performance of the research, data analysis, and the writing of the paper. N.I. participated in research design, performance of the research, and the writing of the paper. K.L. participated in the performance of the research and the writing of the paper. T.B. participated in data analysis and the writing of the paper. D.J. participated in research design and the writing of the paper. B.M. participated in the performance of the research and the writing of the paper. J.U. participated in the performance of the research. S.C. par- ticipated in the performance of the research and writing of the paper. D.L. participated in the performance of the research. S.B. participated in the performance of the research and the writing of the paper. R.R. participated in the performance of the research. C.S. participated in research design, data analysis and the writing of the paper. Received 21 May 2012. Revision requested 13 June 2012. Accepted 12 July 2012. Copyright * 2012 by Lippincott Williams & Wilkins ISSN: 0041-1337/12/9410-1025 DOI: 10.1097/TP.0b013e31826c3985 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.