title: The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients.
abstract: OBJECTIVE
  Cyclosporine A (CsA) is a substrate of cytochrome P450 3A4 (CYP3A4). Recently, a newly discovered intron 6 single-nucleotide polymorphism in CYP3A4 (rs35599367 C>T), defining the CYP3A4*22 allele, has been linked to reduced hepatic expression and activity of CYP3A4. In the present study, the clinical impact of this single-nucleotide polymorphism was investigated in a cohort of patients receiving a CsA-based immunosuppressive regimen.
  
  
  METHODS
  A total of 172 de-novo kidney transplant recipients, receiving CsA/mycophenolate mofetil as immunosuppressive therapy and participating in the Fixed-Dose Concentration Controlled study, were genotyped for the new CYP3A4*22 allele. CsA C(0) and/or C(2) levels were measured on days 3 and 10 and in months 1, 3, 6, and 12 after transplantation. Plasma creatinine concentrations, delayed graft function (DGF), and biopsy-proven acute rejection were recorded.
  
  
  RESULTS
  The CYP3A4*22 allele was significantly associated with a higher risk of DGF compared with the CYP3A4*1/*1 patients after adjustment for known risk factors [odds ratio (OR)=6.34, confidence interval (CI(95%): 1.38-29.3), P=0.015]. Mixed-model analysis demonstrated that the overall creatinine clearance was 20% lower in CYP3A4*22 allele carriers compared with CYP3A4*1/*1 patients [CI(95%) (-33.1 to -7.2%), P=0.002]. For ABCB1 3435C>T, T-variant carriers had a decreased risk of developing DGF compared with CC patients [CT: OR=0.30, CI(95%) (0.11-0.77), P=0.011; TT: OR=0.18, CI(95%) (0.05-0.67), P=0.011].
  
  
  CONCLUSIONS
  CYP3A4*22 constitutes a risk factor for DGF and worse creatinine clearance in patients receiving CsA-based immunosuppressive therapy. Therefore, pretransplant genotyping for the CYP3A4*22 allele might help clinicians to identify patients at risk of DGF and poor renal function when treated with CsA.
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Rachida
authors.initials: R
authors.lastname: Bouamar
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000328:Adult; D002986:Clinical Trials as Topic; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D051799:Delayed Graft Function / Q000139:chemically induced; D005260:Female; D006084:Graft Rejection / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human