Table 2.
Immunosuppressive drugs used in pediatric transplantation and gene polymorphisms related to their effects, metabolism, or transport (Data from organ transplant/kidney diseases studies only).
| Drug | Description | Gene/Protein | Variant | Effect | Study characteristics | References |
|---|---|---|---|---|---|---|
| Corticosteroids | Anti-inflammatory, immunosuppressant | NR3C1/glucocorticoid receptor | rs41423247 | Increased glucocorticoid sensitivity | 95 Japanese renal transplant adults | Miura et al., 2009 |
| CC allele is associated with lower prednisolone | ||||||
| Cmax/Dose (p = 0.021) and lower AUC (p = 0.029) | ||||||
| GR-9β haplotype carriers | Increased incidence of relapse and steroid dependence in children with nephrotic syndrome | 113 children with nephrotic syndrome. | Teeninga et al., 2014 | |||
| Carriers had a higher incidence of steroid dependence (HR 3.05 [95% CI 1.37–6.74] p = 0.006) and frequent relapses (HR 1.98 [95% CI 1.05–3.75], p = 0.036) | ||||||
| Azathioprine | Anti-proliferative | TPMT/Thiopurine methyltransferase | rs1800642 | Life-threatening myelosuppression | 157 adult transplant recipients with TPMT deficiency | Kurzawski et al., 2009 |
| rs1800460 | Associated alleles predicted leukopenia (OR 4.26 [95%CI 1.49–12.1], p = 0.008) | |||||
| rs1142345 | ||||||
| rs56161402 | ||||||
| Mofetil Mycophenolate | Anti-proliferative | CYP2C8/Cytochrome P450 2C8 | rs11572076 | Higher risk of anemia, (Hazard ratio 3.24, 95% CI 1.7–6.2, p = 0.00037) | 978 adult renal transplant recipients | Jacobson et al., 2011 |
| Lower risk of leukopenia in carriers of the wild type genotype (GG vs. GA HR 0.14 [95% CI 0.03–0.59], p = 0.00783) | 189 adult renal transplant | Woillard et al., 2014 | ||||
| UGT2B7/UDP-glucuronosyl-transferase 2B7 | rs7438135 | Increased risk of anemia in GG vs. AA (HR 1.88 [95%CI 1.23–2.88], p = 0.003) | 189 adult renal transplant | Woillard et al., 2014 | ||
| Sirolimus | mTOR inhibitor | CYP3A4/Cytochrome p450 3A4 | rs35599367 | 20% lower metabolic rate in vitro, but no change in pharmacokinetics | 113 adult renal transplant recipients switched from cyclosporine to sirolimus | Woillard et al., 2013 |
| Cyclosporin | Calcineurin inhibitor | CYP3A4/Cytochrome p450 3A4 | rs2740574 | 9% higher oral cyclosporine clearance No impact on cyclosporine pharmacokinetics No impact on cyclosporine pharmacokinetics | 151 adult kidney and heart transplant recipients | Hesselink et al., 2004 |
| rs776746, | CYP3A5 ABCB1/p-glycoprotein | |||||
| rs10264272 | ||||||
| rs1045642 | ||||||
| ABCB1/p-glycoprotein | rs2032582 | 1.3–1.6 higher cyclosporine bioavailability and lower pre-hepatic extraction ratio, only in subjects >8 years | 104 pediatric renal transplant recipients | Fanta et al., 2008 | ||
| s1128503 | ||||||
| XPC/Xeroderma pigmentosum complementation group C | rs2228001 | Cyclosporine nephrotoxicity HR 0.41 [95%CI 0.27–0.63], p = 0.00004 | 323 renal transplant recipients treated with cyclosporine and 692 treated with tacrolimus | Jacobson et al., 2012 | ||
| CYP2C9/Cytochrome p450 2C9 | rs1057910 | Cyclosporine nephrotoxicity | ||||
| HR 3.5 [95%CI 1.91–6.61], p = 0.00006 | ||||||
| PAX4/paired box gene 4 | rs712704 | Cyclosporine nephrotoxicity | ||||
| HR 2.09 [95%CI 1.45–3.01], p = 0.00007 | ||||||
| Tacrolimus | Calcineurin inhibitor | CYP3A4/Cytochrome p450 3A4 | rs3599367 | 50% lower tacrolimus dose requirements in non-CYP3A5 expressers | 129 adult renal transplant recipients (59 tested at 3 months, 80 tested 1–5 years after transplantation) | de Jonge et al., 2014 |
| CYP3A5/Cytochrome p450 3A5 | rs776746 | Tacrolimus chronic toxicity, more frequent in those expressing the enzyme, HR 2.38 [95%CI 1.15–4.92], p = 0.01 | 304 adult renal graft recipients | Kuypers et al., 2010 | ||
| Tacrolimus dose requirement is lower in non-CYP3A5 expressers | 291 renal transplant recipients (124 adults, 167 pediatric) | Garcia-Roca et al., 2012 |