Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population.
Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.
*Unidad de Farmacogenética, Servicio Farmacia, Hospital Universitari i Politècnic La Fe; †Instituto Investigación Sanitaria La Fe; ‡Unidad Central de Investigación, Universidad de Valencia; §Coordinación de Trasplantes, Hospital Universitari i Politècnic La Fe; ¶Servicio de Cardiología, Hospital Universitari i Politècnic La Fe; ‖Servicio de Nefrología, Hospital Universitari i Politècnic La Fe; **CIBER on Liver and Digestive Diseases (CIBERehd), funded by the Instituto de Salud Carlos III, Madrid; de Medicina Digestiva, Hospital Universitari i Politècnic La Fe; ††Unidad de Trasplante Pulmonar, Hospital Universitari i Politècnic La Fe; ‡‡Unidad de Farmacología Clínica, Hospital Universitari i Politècnic La Fe; and §§Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Virginia
V
Bosó
María J
MJ
Herrero
Enrique
E
Buso
Juan
J
Galán
Luis
L
Almenar
Ignacio
I
Sánchez-Lázaro
Jaime
J
Sánchez-Plumed
Sergio
S
Bea
Martín
M
Prieto
María
M
García
Amparo
A
Pastor
Amparo
A
Sole
José Luis
JL
Poveda
Salvador F
SF
Aliño
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013030:Spain; D014019:Tissue Donors; D066027:Transplant Recipients; D000090264:UDP-Glucuronosyltransferase 1A9; D044465:White People / Q000235:genetics*
C000715087:ABCC2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D027361:Organic Anion Transporters; C000715591:UGT1A9 protein, human; D003577:Cytochrome P-450 Enzyme System; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; C022745:thiopurine methyltransferase; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9