SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients

Abstract

Background: The impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT.

Materials and methods: The feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3' untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs).

Results: Of all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48-23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers.

Conclusion: Our results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.