IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients
| Autor: | Zhao-Qian Liu, Hua-Wen Xin, Wei Zhang, Yong-Fang Hu, Hai-Yan He, Fa-Zhong He, Xiao-Ping Chen, Hong-Hao Zhou, Ying-zi Ming, Zhiying Luo, Ming-Jie Shao, Mou-Ze Liu, Jian-Quan Luo, Yue-Li Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Graft Rejection Male medicine.medical_specialty chemical and pharmacologic phenomena Single-nucleotide polymorphism Pharmacology Biology Polymorphism Single Nucleotide 030226 pharmacology & pharmacy Tacrolimus 03 medical and health sciences 0302 clinical medicine Asian People Pharmacokinetics Internal medicine Genotype medicine Humans CTLA-4 Antigen Pharmacology (medical) CYP3A5 Kidney transplantation CYP3A4 General Medicine Middle Aged medicine.disease Kidney Transplantation Endocrinology Pharmacogenetics 030220 oncology & carcinogenesis Female Interleukin-3 Original Article Immunosuppressive Agents |
| Zdroj: | Acta Pharmacologica Sinica. 38:415-423 |
| ISSN: | 1745-7254 1671-4083 |
| Popis: | The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account. |
| Databáze: | OpenAIRE |
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