title: NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation.
abstract: 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.
  
  
  OBJECTIVE
  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 significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/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, 1.33-7.73]; P=0.006). No significant difference in geometric 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 pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.
authors.affiliation: Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Barraclough
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Isbel
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Lee
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.forename: Scott B
authors.initials: SB
authors.lastname: Campbell
authors.forename: Diana R
authors.initials: DR
authors.lastname: Leary
authors.forename: Seweryn
authors.initials: S
authors.lastname: Bialasiewicz
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Rockett
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
mesh_terms: D000328:Adult; D001739:BK Virus; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D015994:Incidence; D016030:Kidney Transplantation / Q000276:immunology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011239:Prednisolone / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D011379:Prognosis; D011446:Prospective Studies; D011987:Receptors, Steroid / Q000235:genetics*; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014766:Viremia / Q000150:complications* / Q000453:epidemiology
chemical_list: D007166:Immunosuppressive Agents; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus