当前位置： SCI文献检索 > Pharmacogenetics and Genomics期刊下所有文献 > Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.

Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.

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<0.0001; validation group: β=0.02 g/l, P=0.0002) and triglyceride levels (discovery group: β=0.02 g/l, P=0.0059; validation group: β=0.05 g/l, P=0.0370). Sirolimus trough levels were also associated with an increased risk for cutaneous adverse events [odds ratio=1.97, 95% confidence interval (1.32-1.94), P=0.0009] and oedemas [odds ratio=1.16, 95% confidence interval (1.03-1.30), P=0.01342] in the discovery group, but this was not confirmed in the validation group. CONCLUSION:These results provide evidence of an association between an m-TOR haplotype and a decrease in haemoglobin in renal transplant recipients.

journal_name

Pharmacogenet Genomics

journal_title

Pharmacogenetics and genomics

authors

Woillard JB,Kamar N,Rousseau A,Rostaing L,Marquet P,Picard N

doi

10.1097/FPC.0b013e328357359d

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

725-32

issue

eissn

1744-6872

issn

1744-6880

journal_volume

pub_type

杂志文章,多中心研究,随机对照试验

在线工具

Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.