title: Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.
abstract: BACKGROUND
  Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.
  
  
  METHODS
  Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.
  
  
  RESULTS
  Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).
  
  
  CONCLUSIONS
  Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.
authors.affiliation: aDepartments of Biostatistics bDepartment of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee cUniversity of Rochester Medical Center, Center for Human Experimental Therapeutics, Rochester dDepartment of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York eDepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama fDepartment of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California gCase Western Reserve University, Department of Epidemiology and Biostatistics, Cleveland, Ohio, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Wanga
authors.forename: Charles
authors.initials: C
authors.lastname: Venuto
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Shepherd
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D003404:Creatinine / Q000097:blood*; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003404:Creatinine; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D019438:Ritonavir; D000068698:Tenofovir; D000099227:Abacavir; C098320:efavirenz