title: Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium.
abstract: BACKGROUND
  The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in whites relative to African Americans (AA).
  
  
  METHODS
  We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single-nucleotide polymorphism chip with 2722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a seven-center consortium.
  
  
  RESULTS
  During the 6-month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4-8.4) ng/mL vs. 8.3 (6.4-10.4) ng/mL (P<0.0001), despite 60% higher daily doses, 8 (5-10) mg vs. 5 (4-7) mg (P<0.0001). The median tacrolimus trough concentration in week 1 posttransplant was particularly low in AAs (2.1 [1.2-3.5] ng/mL) compared with non-AAs (5.0 [3.1-8.2] ng/mL) (P<0.0001), despite similar initial doses. In single-variant analysis, CYP3A5*3 (rs776746) was the top variant (P=2.4×10) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, 35 additional variants were identified (P<0.01, not significant at false discovery rate 20%). In the final multivariant, regression models beginning with these variants and clinical factors, seven variants were identified in the non-AA and seven variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations.
  
  
  CONCLUSIONS
  We identified variants beyond CYP3A5*3, which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. jacob117@umn.edu
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
authors.forename: Ann M
authors.initials: AM
authors.lastname: Brearley
authors.forename: Robert
authors.initials: R
authors.lastname: Leduc
authors.forename: Weihau
authors.initials: W
authors.lastname: Guan
authors.forename: David
authors.initials: D
authors.lastname: Schladt
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
authors.forename: Vishal
authors.initials: V
authors.lastname: Lamba
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.forename: Rosalyn B
authors.initials: RB
authors.lastname: Mannon
authors.forename: Ajay
authors.initials: A
authors.lastname: Israni
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus