Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

Abstract

Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventyfive renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C min /[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to

A Machine Learning-Based Identification of Genes Affecting the Pharmacokinetics of Tacrolimus Using the DMETTM Plus Platform

“…rs776746 or CYP3A5*3 is located in the terminal sequence of the CYP3A5 s intron 3 (Table 1) and induces a premature termination codon. Therefore, subjects carrying rs776746 have an increased systemic exposure to tacrolimus caused by the reduced metabolism of tacrolimus by CYP3A5 as shown in the present studies [19][20][21][22][23][24].…”

Utilization of an Emr-Biorepository to Identify the Genetic Predictors of Calcineurin-Inhibitor Toxicity in Heart Transplant Recipients

“…SNP CYP2A6 rs28399433 also met the 0.05 threshold (coef(S.E) = 20.91(3.46), p = 0.02) in unadjusted analyses. Two of these associations maintained significance at the 0.05 threshold in the multivariate models CYP3A5 rs776746 (coef(S.E) = 14.60(6.41), p = 0.03) and CYP2A6 rs28399433 (coef(S.E) = 17.14(8.24), p = 0.04)[19]. In analyses extended to the full dataset regardless of race/ethnicity, only CYP2A6 rs28399433 (coef(S.E) = 17.46(6.70), p = 0.01) approached significance in the adjusted analysis (data not shown).…”

Pharmacogenetics of Immunosuppressants in Solid Organ Transplantation: Time to Implement in the Clinic

“…In the group of CYP3A5 nonexpressers (expressers were excluded to avoid its influence), there was a direct correlation with an increase in Cmin/D TAC blood levels and CYP2C19*2/*2 genotype, which also showed allograft delayed function (acute tubular necrosis in 3 out of 4 patients). So CYP2C19*2/*2 variant indirectly elicits an increase of TAC blood levels in CYP3A5 nonexpressers and may lead to adverse events [3].…”

“…However, TDM is only possible after the drug is administered and steady state and patient's compliance are achieved; thus, complementary strategies are needed. The intra-and inter-patient differences in immunosuppressant dosage requirements and pharmacokinetics are attributable to several factors, such as kidney function, ethnicity, concomitant use of other drugs [3], and qualitative and quantitative changes of proteins whose activity plays key roles in the absorption, distribution, metabolism, and function of these drugs. In these last mentioned protein changes is where pharmacogenetics plays a crucial role: Functional changes of these proteins (transporters, metabolizing enzymes, target proteins, etc.)…”