Donor Genotype and Intragraft Expression of CYP3A5 Reflect the Response to Steroid Treatment During Acute Renal Allograft Rejection
| Autor: | Emile de Heer, Johan W. de Fijter, Nils Lachmann, Marian C. Clahsen-van Groningen, Niels Vincent Rekers, Marko J.K. Mallat, Michael Eikmans, Reinhold Kreutz, Malu Zandbergen, Jianxin Yang, Tanja Flaig, Juliane Bolbrinker, Frans H.J. Claas, Ingeborg M. Bajema, Susanne Brakemeier, Klemens Budde, Marijke J. Spruyt-Gerritse, Jacqueline D.H. Anholts |
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| Přispěvatelé: | Pathology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Graft Rejection Male Genotype Pharmacogenomic Variants Drug Resistance Kaplan-Meier Estimate Kidney Methylprednisolone Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine Gene Frequency Risk Factors Germany Genetic predisposition Odds Ratio Medicine Cytochrome P-450 CYP3A Humans RNA Messenger Risk factor CYP3A5 Gene Glucocorticoids Netherlands Proportional Hazards Models Transplantation Chi-Square Distribution business.industry Middle Aged Allografts Kidney Transplantation Tissue Donors Pharmacogenomic Testing surgical procedures operative 030104 developmental biology Steroid therapy Logistic Models Phenotype Treatment Outcome Pharmacogenetics 030220 oncology & carcinogenesis Immunology Acute Disease Renal allograft Female business |
| Zdroj: | Transplantation, 101(9), 2017-2025 Transplantation, 101(9), 2017-2025. Lippincott Williams & Wilkins |
| ISSN: | 1534-6080 0041-1337 |
| Popis: | Glucocorticoid (GC)-refractory acute rejection (AR) is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection.Single nucleotide polymorphisms of genes involved in GC signaling (GR, GLCCI1) and drug metabolism and transport (CYP3A5, ABCB1, and PXR) were analyzed in kidney transplant recipients (1995-2005, Leiden cohort, n = 153) treated with methylprednisolone. Significant associations were verified in a second cohort (Berlin cohort, n = 66).Patients who received a CYP3A5*1 allele expressing allograft had a lower risk of resistance to methylprednisolone during AR (odds ratio, 0.29; 95% confidence interval, 0.11-0.79; P = 0.016 in combined cohorts analysis). No differences were observed for GC signaling or other drug metabolism/transport-related genes. Both before transplantation (n = 69) and at time of AR (n = 88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A5*1 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P0.00001). Moreover, steroid-responsive patients (n = 64) expressed significantly higher intragraft CYP3A5 mRNA levels compared to steroid-refractory patients (n = 42) in AR (P = 0.006).CYP3A5 protein expression was detected in tubular epithelial cells and inflammatory cells within the grafts. Our findings show that steroid resistance during AR is associated with donor genotype and intragraft expression levels of CYP3A5. |
| Databáze: | OpenAIRE |
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