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.

MATERIALS AND 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].

CONCLUSION:

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: Laure Elens, Rachida Bouamar, Dennis A Hesselink, Vincent Haufroid, Teun van Gelder, Ron H N van Schaik
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 22 Issue 5 Pg. 373-80 (May 2012) ISSN: 1744-6880 [Electronic] United States
• PMID: 22388796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Cyclosporine
• Creatinine
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• Adult
• Clinical Trials as Topic
• Creatinine (blood)
• Cyclosporine (administration & dosage, adverse effects, pharmacokinetics)
• Cytochrome P-450 CYP3A (genetics)
• Delayed Graft Function (chemically induced)
• Female
• Graft Rejection (genetics)
• Humans
• Immunosuppressive Agents (administration & dosage, blood, pharmacokinetics)
• Kidney Transplantation (adverse effects)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)