Purpose: Risk for acute rejection (AR) complicating transplant immunosuppression may be affected by frequent variants in pharmacogenes. Using a DNA biobank linked to electronic medical records (EMR), we explored associations between drug absorption, distribution, metabolism, and elimination (ADME) gene variants and acute rejection.

Methods: We identified 514 potential study subjects and genotyped for 1,936 ADME variants (DMET Plus, Affymetrix) plus another 91 variants in CYP3A4 and NR1I2 (iPlex Gold, Sequenom). A panel of 360 ancestry informative markers was also used to calculate genetic ancestry. After quality control and limiting to subjects with transplant biopsies for clinical cause, 135 individuals remained. The primary outcome was biopsy proven AR. Race stratified analyses (Black n=40, White n=95) were performed with Cox regression adjusting for ancestry and potential confounders. Meta-analysis across racial groups was performed using random effects models.

Results: There were 45 White subjects (mean age 40.8, 36% female, mean 863 days post transplant) and 22 Black subjects (mean age 42.1, 56% female, mean 873 days post transplant) with AR. In race-stratified analyses, no variants were significantly associated with AR. The lowest p value in White subjects was for rs2235040 in ABCB1 (p= 0.001), and in Blacks subjects rs1799836 in MAOB, rs2070959 in UGT1A6, and rs10929302 in UGT1A1 (all p= 0.0002). In meta-analyses, lowest p values were for rs2231142 in ABCG2 (meta-hazard ratio [HR] 0.33, meta-p= 3.45 x 10^-13) and rs7311358 in SLCO1B3 (meta-HR 0.46, meta-p= 3.23 x 10^-5), both nonsynonymous variants previously associated with mycophenolate pharmacokinetics in kidney transplant recipients.

Conclusions: Using DNA biobank linked to EMR, we found two ADME variants to be significantly associated with decreased risk of AR in kidney transplant recipients. Both have been associated with mycophenolate pharmacokinetics. Replication of these associations is warranted.

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