Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.: sirolimus and m-TOR pathway polymorphismsReport as inadecuate




Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.: sirolimus and m-TOR pathway polymorphisms - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 PIST - Pharmacologie des Immunosuppresseurs et de la Transplantation 2 Service de Pharmacologie, toxicologie et pharmacovigilance CHU Limoges 3 Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation 4 Centre de Physiopathologie Toulouse Purpan

Abstract : BACKGROUND: The mammalian target of rapamycin m-TOR inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor and p70S6K, sirolimus dose and exposure, and other time-independent as well as time-dependent covariates, with sirolimus-induced adverse events in kidney transplant recipients. METHODS: This study included a first group of 113 patients, switched from a calcineurin inhibitor to sirolimus, and a validation group of 66 patients from another clinical trial, with the same immunosuppressive regimen. The effects of gene polymorphisms and covariates on the total cholesterol, LDL cholesterol, triglycerides, haemoglobin, cutaneous adverse events, oedemas and infections were studied using multilinear regression, or logistic regression imbedded in linear mixed-effect models. RESULTS: An m-TOR variant haplotype was significantly associated with a decrease in haemoglobin levels in the two populations of patients discovery group: β=-0.82 g-dl, P=0.0076; validation group: β=-1.58 g-dl, P=0.0308. Increased sirolimus trough levels were significantly associated with increased total cholesterol levels discovery group: β=0.02 g-l, P



Author: Jean-Baptiste Woillard - Nassim Kamar - Annick Rousseau - Lionel Rostaing - Pierre Marquet - Nicolas Picard -

Source: https://hal.archives-ouvertes.fr/



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