Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function
After liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies a...
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00528/full |
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| author | Yuan Liu Chengdong Zhang Lei Li Baochi Ou Liyun Yuan Tao Zhang Junwei Fan Zhihai Peng |
| author_facet | Yuan Liu Chengdong Zhang Lei Li Baochi Ou Liyun Yuan Tao Zhang Junwei Fan Zhihai Peng |
| author_sort | Yuan Liu |
| collection | DOAJ |
| description | After liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies as a result of variations in its metabolism. The effects of genetic and clinical factors on the plasma concentration of tacrolimus appear to differ in the CP and SP. To establish a model explaining the variation in tacrolimus trough concentration between individuals in the CP and SP, we conducted a retrospective, single-center, discovery study of 115 pairs of patients (115 donors and 115 matched recipients) who had undergone liver transplantation. Donors and recipients were genotyped by a genome-wide association study (GWAS) using an exome chip. Novel exons were identified that influenced tacrolimus trough concentrations and were verified with bootstrap analysis. In donors, two single-nucleotide polymorphisms showed an effect on the CP (rs1927321, rs1057192) and four showed an effect on the SP (rs776746, rs2667662, rs7980521, rs4903096); in recipients, two single-nucleotide polymorphisms showed an effect in the SP (rs7828796, rs776746). Genetic factors played a crucial role in tacrolimus metabolism, accounting for 44.8% in the SP, which was higher than previously reported. In addition, we found that CYP3A5, which is known to affect the metabolism of tacrolimus, only influenced tacrolimus pharmacokinetics in the SP. |
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| language | English |
| last_indexed | 2024-04-13T15:11:02Z |
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| spelling | doaj.art-6ff455ae1e2c4c149e42f08ca121628b2022-12-22T02:42:00ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-05-011010.3389/fgene.2019.00528437610Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver FunctionYuan Liu0Chengdong Zhang1Lei Li2Baochi Ou3Liyun Yuan4Tao Zhang5Junwei Fan6Zhihai Peng7Department of Hepatobiliary Pancreatic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, ChinaDepartment of Hepatobiliary Pancreatic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Hepatobiliary Pancreatic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaKey Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Organ Transplant, The Second Affiliated Hospital to Guangzhou Medical University, Guangzhou, ChinaDepartment of Hepatobiliary Pancreatic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Hepatobiliary Pancreatic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaAfter liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies as a result of variations in its metabolism. The effects of genetic and clinical factors on the plasma concentration of tacrolimus appear to differ in the CP and SP. To establish a model explaining the variation in tacrolimus trough concentration between individuals in the CP and SP, we conducted a retrospective, single-center, discovery study of 115 pairs of patients (115 donors and 115 matched recipients) who had undergone liver transplantation. Donors and recipients were genotyped by a genome-wide association study (GWAS) using an exome chip. Novel exons were identified that influenced tacrolimus trough concentrations and were verified with bootstrap analysis. In donors, two single-nucleotide polymorphisms showed an effect on the CP (rs1927321, rs1057192) and four showed an effect on the SP (rs776746, rs2667662, rs7980521, rs4903096); in recipients, two single-nucleotide polymorphisms showed an effect in the SP (rs7828796, rs776746). Genetic factors played a crucial role in tacrolimus metabolism, accounting for 44.8% in the SP, which was higher than previously reported. In addition, we found that CYP3A5, which is known to affect the metabolism of tacrolimus, only influenced tacrolimus pharmacokinetics in the SP.https://www.frontiersin.org/article/10.3389/fgene.2019.00528/fullGWASCYP3A5exometacrolimusFAM26F |
| spellingShingle | Yuan Liu Chengdong Zhang Lei Li Baochi Ou Liyun Yuan Tao Zhang Junwei Fan Zhihai Peng Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function Frontiers in Genetics GWAS CYP3A5 exome tacrolimus FAM26F |
| title | Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function |
| title_full | Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function |
| title_fullStr | Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function |
| title_full_unstemmed | Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function |
| title_short | Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function |
| title_sort | genome wide association study of tacrolimus pharmacokinetics identifies novel single nucleotide polymorphisms in the convalescence and stabilization periods of post transplant liver function |
| topic | GWAS CYP3A5 exome tacrolimus FAM26F |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00528/full |
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