Rebecca A Pulk1, David S Schladt2, William S Oetting1, Weihua Guan3, Ajay K Israni2, Arthur J Matas4, Rory P Remmel5, Pamala A Jacobson1. 1. Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA. 2. Department of Nephrology & Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, MN, USA. 3. Division of Biostatistics, School of Public Health, University of Minnesota, MN, USA. 4. Division of Transplantation, Department of Surgery, University of Minnesota, MN, USA. 5. Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, MN, USA.
Abstract
AIM: Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition. PATIENTS & METHODS: We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). RESULTS: Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10(-75)). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated. CONCLUSION: This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 2015.
AIM: Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition. PATIENTS & METHODS: We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). RESULTS: Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10(-75)). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated. CONCLUSION: This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 2015.
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