The Association Between CYP3A4,CYP3A5,ABCB1 Genetic Polymorphisms And Kidney Grafe Rejection,CNI-related Adverse Events

PurposeThe reaction of renal transplant recipients to Calcineurin Inhibitor is different personaly, CYP3A4 (Cytochrome P450 3A4),CYP3A5,ABCB1(ATP binding cassette B1) genetic polymorphisms influence CNI pharmacokinetics. This study investigated the effects of ABCB1, CYP3A4*18B and CYP3A5*3 genetic polymorphisms on acute cellular rejection,chronic rejection and anti-HLA antibody positive and anti-MICA antibody positive; investigated the effects of ABCB1, CYP3A4*18B and CYP3A5*3 genetic polymorphisms on nephrotoxicity of calcineurin inhibitors in kidney transplant patients post-transplantation diabetes mellitus and pneumonia in one year after kidney transplant;in order to guide treatment individually.MethodsWe selected 208 patients who had done kidney transplant operation from 1990 year to 2009 year,ABCB1 C1236T,G2677T/A, C3435T, CYP3A4*18B, and CYP3A5*3 genotypes were determined by direct sequencing method. Presence of anti-HLA class I and II and anti-MICA antibodies was determined by Luminex microbeads technology (Luminex Corporation, Austin, TX) using LABScreen Mixed. Retrospective case control study was utilized to identify the association between CYP3A4*18B,CYP3A5*3,ABCB1 genetic polymorphisms and drug action,adverse reaction.Result1 significant differences were observed in acute cellular rejection between the subjects with the CYP3A4 AA genotype and those with GG genotype (P=0.016) as well as between the subjects with the CYP3A4/5 AA-AA genotype and those with GG-GG genotype (P=0.046);but there were no differences in acute cellular rejection between the subjects with the ABCB1 exon12,21,26 wild genotype and those with variation genotype; significant differences were observed in anti-MICA antibodies positive between the subjects with the CYP3A4,CYP3A5 AA genotype or ABCB1 exonl2 CT/TT genotype and those with AG/GG genotype or CC genotype (P<0.001), but no differences were observed in anti-MICA antibodies between the subjects with the ABCB1 exon21,26 wild genotype and those with variation genotype; ignificant differences were observed in chronic rejection between anti-HLA class I antibodies positive and negative (P=0.027) as well as between anti-HLA class I and II antibodies positive and negative (P=0.035), but no differences were observed between anti-MICA antibodies positive and negative; CYP3A4,CYP3A5 and ABCB1 exon12,21,26 genetic polymorphisms were not associated with chronic rejection.2 CYP3A4. CYP3A5 and ABCB1 exon12,21,26 genetic polymorphisms were not associated with nephrotoxicity of calcineurin inhibitors.3 CYP3A4,CYP3A5 and ABCB1 exon12,21,26 genetic polymorphisms were not associated with pneumonia in one year after kidney transplant; no significant differences were observed in PTDM between the subjects with the CYP3A4 or CYP3A5 wild genotype and those with variation genotype, ABCB1 exonl2 but not exon 21,26 were associated with PTDM (P=0.043), also significant differences were observed in PTDM between the subjects with the ABCB1 exonl2,21,26 CC-GG-CC genotype and those with TT-TT-TT genotype.ConclusionsThis study demonstrated that CYP3A4 and CYP3A5 genetic polymorphisms but not ABCB1 genetic polymorphisms were associated with acute cellular rejection; CYP3A4,CYP3A5 and ABCB1 exonl2 genetic polymorphisms affected positive of anti-MICA antibodies; CYP3A4 CYP3A5 and ABCB1 genetic polymorphisms were not associated with nephrotoxicity of calcineurin inhibitors and pneumonia in one year after kidney transplant, while ABCB1 exon12 genetic polymorphisms but not other genetic polymorphisms were associated with PTDM. These consequence demonstrated that CYP3A4,CYP3A5 and ABCB1 genetic polymorphisms affected the reaction of renal transplant recipients to Calcineurin Inhibitor, so CYP3A4,CYP3A5 and ABCB1 genetic polymorphisms were helpful to clinic treatment individually.