Genotype and Allele Frequencies of Drug-Metabolizing Enzymes and Drug Transporter Genes Affecting Immunosuppressants in the Spanish White Population

Abstract

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.

Genotype and allele frequencies of TYMS rs2790 A > G polymorphism in a Chinese paediatric population with acute lymphoblastic leukaemia

“…frequencies. 15 The allele and genotype frequencies for the rs2790 A > G polymorphism observed in our study were in accordance with the predicted frequencies calculated by the Hardy-Weinberg law.…”

“…21 However, the 3R allele significantly reduced the risks of leukocytopenia and thrombocytopenia in 167 22 Additionally, a reduced EFS for 3R homozygotes was found in patients with ALL. 15 The 3R/3R genotype significantly increased the risk of haematological relapse in 246 children with ALL. 23 Due to the narrow therapeutic index of MTX, concentration monitoring for MTX was routinely performed in paediatric patients with ALL to avoid severe toxicity caused by excessive exposure.…”

“…The relevance of a given variant could be different in populations with different variant frequencies 15. However, MTX did not exert satisfactory effects in certain patients, due to the development of severe toxicity.…”

Recipient Uridine 5′-Diphospho-glucuronosyltransferase UGT1A9 c.98T>C Variant Determines Transplanted Kidney Filtration Rate

“…The frequency of the UGT1A9 c.98C allele is 1% to 4% in the Caucasian population [5,11], and 1.6% in the Polish population, according to the study by Zakerska et al [12]. We found a similar frequency of the analyzed allelic variant (1.7%) in the study group of kidney transplant recipients [10].…”

Study on the association of UGT1A9 gene c.98T>C polymorphism and mycophenolic acid plasma levels in renal transplant patients

“…Studies by van Schaik et al (2009) andBosó et al (2014), performed in Caucasian populations (with 338 and 570 renal transplant patients, respectively) showed a frequency of the UGT1A9 allele c.98C between 1 and 4%. A study conducted by Zakerska et al (2013) with 308 Polish patients showed that 1.6% of the study population carried the c.98C allele.…”