Association between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients

Abstract

Renal dysfunction continues to be a major challenge associated with calcineurin inhibitor (CNI) therapy. The goal of this study was to assess the relationship between single nucleotide variants (SNVs) in CNI pharmacokinetic (PK) and pharmacodynamic (PD) genes and renal dysfunction in adult heart transplant (HTx) recipients. This retrospective analysis included n=194 patients receiving a CNI at one year post-HTx. Using a candidate gene approach, 10 SNVs in 5 PK genes and 31 SNVs in 17 PD genes were selected for investigation. SNVs were analyzed as wild-type homozygotes versus variant carriers. Estimated glomerular filtration rate (eGFR) and relevant clinical data were extracted from the electronic medical record. The primary endpoint was renal dysfunction, defined as an eGFR <45 mL/min/1.73m2 calculated by the MDRD formula, at one year post-HTx. Univariate analysis was performed using Chi-Square tests, with significant SNVs (p<0.05) considered for the multivariate analysis. Multivariate analysis was performed using logistic regression, with body mass index, type of CNI (tacrolimus vs cyclosporine) at one year post-HTx, age at transplant, race (white vs non-white), and pre-transplant eGFR as covariates. The study consisted of 77% men and 79% Caucasians (mean age at HTx= 50 ± 12 years). At one year post-HTx, 54% of patients were receiving tacrolimus and 29% had renal dysfunction. The tag-SNV, rs4803455 C>A in transforming growth factor beta 1 (TGFB1; A allele frequency=45%), was the only variant significantly associated with renal function (p=0.004) in the univariate analysis. Renal dysfunction was present in 43% of patients with the C/C genotype and 22% of subjects with at least one variant A allele. This SNV remained significant in the multivariate model, with patients with at least one variant A allele having lower odds of renal dysfunction compared to C/C patients (odds ratio 0.41, 95% CI 0.19-0.84, p=0.02). Our data suggest that the TGFB1 rs4803455 variant A allele provides protection from renal dysfunction in adult HTx recipients receiving CNIs. Further studies are needed to determine the causal variant in linkage with rs4803455 in order to elucidate the functional mechanisms by which it influences renal function following HTx.