Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients
The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver...
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| Veröffentlicht in: | International immunopharmacology 2018-04, Vol.57, p.18-24 |
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| creator | Liu, Jianyu Ouyang, Yabo Chen, Dexi Yao, Bo Lin, Dongdong Li, Zhiqiang Zang, Yunjin Liu, Huan Fu, Xiaoyue |
| description | The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.
•The C/D ratio was higher when the recipient genotype of rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C in 3 months.•The C/D ratio was higher when donor with the rs776746 G/G or rs15524 T/T or rs4646450 C/C all through one year.•The donor genotype polymorphism had greater influence on the Tac C/D ratio than the recipient genotype. |
| doi_str_mv | 10.1016/j.intimp.2018.02.005 |
| format | Article |
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•The C/D ratio was higher when the recipient genotype of rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C in 3 months.•The C/D ratio was higher when donor with the rs776746 G/G or rs15524 T/T or rs4646450 C/C all through one year.•The donor genotype polymorphism had greater influence on the Tac C/D ratio than the recipient genotype.</description><identifier>ISSN: 1567-5769</identifier><identifier>EISSN: 1878-1705</identifier><identifier>DOI: 10.1016/j.intimp.2018.02.005</identifier><identifier>PMID: 29454235</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adolescent ; Adult ; Aged ; Alleles ; China ; Cytochrome ; Cytochrome P-450 CYP3A - genetics ; Cytochrome P450 ; Donors ; Drugs ; Female ; Genotype ; Genotype & phenotype ; Genotypes ; Graft rejection ; Graft Rejection - drug therapy ; Graft Rejection - genetics ; Graft Survival - genetics ; Histocompatibility - genetics ; Humans ; Immunology ; Immunosuppressive agents ; Immunosuppressive Agents - therapeutic use ; Intestine ; Liver ; Liver Transplantation ; Male ; Middle Aged ; P450 ; Patients ; Pharmacogenomics ; Pharmacology ; Polymorphism ; Polymorphism, Single Nucleotide ; Single-nucleotide polymorphism ; SNP ; Statistical analysis ; Substrates ; Tacrolimus ; Tacrolimus - therapeutic use ; Tissue Donors ; Transplantation ; Transplants & implants ; Treatment Outcome ; Young Adult</subject><ispartof>International immunopharmacology, 2018-04, Vol.57, p.18-24</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier BV Apr 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-6d16a4c7cc655b3c712d2bd2467b93357b883b90d0e01cbb9e1338be8c9e50af3</citedby><cites>FETCH-LOGICAL-c390t-6d16a4c7cc655b3c712d2bd2467b93357b883b90d0e01cbb9e1338be8c9e50af3</cites><orcidid>0000-0001-5338-1263 ; 0000-0001-8049-6779</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1567576918300547$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29454235$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Jianyu</creatorcontrib><creatorcontrib>Ouyang, Yabo</creatorcontrib><creatorcontrib>Chen, Dexi</creatorcontrib><creatorcontrib>Yao, Bo</creatorcontrib><creatorcontrib>Lin, Dongdong</creatorcontrib><creatorcontrib>Li, Zhiqiang</creatorcontrib><creatorcontrib>Zang, Yunjin</creatorcontrib><creatorcontrib>Liu, Huan</creatorcontrib><creatorcontrib>Fu, Xiaoyue</creatorcontrib><title>Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients</title><title>International immunopharmacology</title><addtitle>Int Immunopharmacol</addtitle><description>The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.
•The C/D ratio was higher when the recipient genotype of rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C in 3 months.•The C/D ratio was higher when donor with the rs776746 G/G or rs15524 T/T or rs4646450 C/C all through one year.•The donor genotype polymorphism had greater influence on the Tac C/D ratio than the recipient genotype.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Alleles</subject><subject>China</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Cytochrome P450</subject><subject>Donors</subject><subject>Drugs</subject><subject>Female</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Genotypes</subject><subject>Graft rejection</subject><subject>Graft Rejection - drug therapy</subject><subject>Graft Rejection - genetics</subject><subject>Graft Survival - genetics</subject><subject>Histocompatibility - genetics</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunosuppressive agents</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Intestine</subject><subject>Liver</subject><subject>Liver Transplantation</subject><subject>Male</subject><subject>Middle Aged</subject><subject>P450</subject><subject>Patients</subject><subject>Pharmacogenomics</subject><subject>Pharmacology</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Single-nucleotide polymorphism</subject><subject>SNP</subject><subject>Statistical analysis</subject><subject>Substrates</subject><subject>Tacrolimus</subject><subject>Tacrolimus - therapeutic use</subject><subject>Tissue Donors</subject><subject>Transplantation</subject><subject>Transplants & implants</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>1567-5769</issn><issn>1878-1705</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAQgCMEoqXwBghZ4sIlyziO83NBQlsoSJXgAGfLsSfdWSV2sJ2V-hY8Mo62cOgBX8a2vvmxv6J4zWHHgTfvjztyieZlVwHvdlDtAOST4pJ3bVfyFuTTvJdNW8q26S-KFzEeAfJ9zZ8XF1Vfy7oS8rL4fe2dD0w7ywIaWghdYt9rCewOHbLFT_ezD8uB4hwZuXFa0RnMO0snsque2HLQYdbGT_6OTD7jOKJJkfmRJW2Cn2het1S2P5DDiGyiEwaWgnZxmbRLOpF3bMkh944vi2ejniK-eohXxc_Pn37sv5S3326-7j_elkb0kMrG8kbXpjWmkXIQpuWVrQZb1U079ELIdug6MfRgAYGbYeiRC9EN2JkeJehRXBXvznWX4H-tGJOaKRqc8kTo16gqAAF13UGT0beP0KNfg8vTZarZluxkpuozld8cY8BRLYFmHe4VB7UZU0d1NqY2YwoqlY3ltDcPxddhRvsv6a-iDHw4A5h_40QYVDS0SbCUjSVlPf2_wx_UAKwz</recordid><startdate>201804</startdate><enddate>201804</enddate><creator>Liu, Jianyu</creator><creator>Ouyang, Yabo</creator><creator>Chen, Dexi</creator><creator>Yao, Bo</creator><creator>Lin, Dongdong</creator><creator>Li, Zhiqiang</creator><creator>Zang, Yunjin</creator><creator>Liu, Huan</creator><creator>Fu, Xiaoyue</creator><general>Elsevier B.V</general><general>Elsevier BV</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5338-1263</orcidid><orcidid>https://orcid.org/0000-0001-8049-6779</orcidid></search><sort><creationdate>201804</creationdate><title>Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients</title><author>Liu, Jianyu ; Ouyang, Yabo ; Chen, Dexi ; Yao, Bo ; Lin, Dongdong ; Li, Zhiqiang ; Zang, Yunjin ; Liu, Huan ; Fu, Xiaoyue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-6d16a4c7cc655b3c712d2bd2467b93357b883b90d0e01cbb9e1338be8c9e50af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Alleles</topic><topic>China</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Cytochrome P450</topic><topic>Donors</topic><topic>Drugs</topic><topic>Female</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Genotypes</topic><topic>Graft rejection</topic><topic>Graft Rejection - drug therapy</topic><topic>Graft Rejection - genetics</topic><topic>Graft Survival - genetics</topic><topic>Histocompatibility - genetics</topic><topic>Humans</topic><topic>Immunology</topic><topic>Immunosuppressive agents</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Intestine</topic><topic>Liver</topic><topic>Liver Transplantation</topic><topic>Male</topic><topic>Middle Aged</topic><topic>P450</topic><topic>Patients</topic><topic>Pharmacogenomics</topic><topic>Pharmacology</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Single-nucleotide polymorphism</topic><topic>SNP</topic><topic>Statistical analysis</topic><topic>Substrates</topic><topic>Tacrolimus</topic><topic>Tacrolimus - therapeutic use</topic><topic>Tissue Donors</topic><topic>Transplantation</topic><topic>Transplants & implants</topic><topic>Treatment Outcome</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Jianyu</creatorcontrib><creatorcontrib>Ouyang, Yabo</creatorcontrib><creatorcontrib>Chen, Dexi</creatorcontrib><creatorcontrib>Yao, Bo</creatorcontrib><creatorcontrib>Lin, Dongdong</creatorcontrib><creatorcontrib>Li, Zhiqiang</creatorcontrib><creatorcontrib>Zang, Yunjin</creatorcontrib><creatorcontrib>Liu, Huan</creatorcontrib><creatorcontrib>Fu, Xiaoyue</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International immunopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Jianyu</au><au>Ouyang, Yabo</au><au>Chen, Dexi</au><au>Yao, Bo</au><au>Lin, Dongdong</au><au>Li, Zhiqiang</au><au>Zang, Yunjin</au><au>Liu, Huan</au><au>Fu, Xiaoyue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients</atitle><jtitle>International immunopharmacology</jtitle><addtitle>Int Immunopharmacol</addtitle><date>2018-04</date><risdate>2018</risdate><volume>57</volume><spage>18</spage><epage>24</epage><pages>18-24</pages><issn>1567-5769</issn><eissn>1878-1705</eissn><abstract>The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.
•The C/D ratio was higher when the recipient genotype of rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C in 3 months.•The C/D ratio was higher when donor with the rs776746 G/G or rs15524 T/T or rs4646450 C/C all through one year.•The donor genotype polymorphism had greater influence on the Tac C/D ratio than the recipient genotype.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>29454235</pmid><doi>10.1016/j.intimp.2018.02.005</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-5338-1263</orcidid><orcidid>https://orcid.org/0000-0001-8049-6779</orcidid></addata></record> |
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| subjects | Adolescent Adult Aged Alleles China Cytochrome Cytochrome P-450 CYP3A - genetics Cytochrome P450 Donors Drugs Female Genotype Genotype & phenotype Genotypes Graft rejection Graft Rejection - drug therapy Graft Rejection - genetics Graft Survival - genetics Histocompatibility - genetics Humans Immunology Immunosuppressive agents Immunosuppressive Agents - therapeutic use Intestine Liver Liver Transplantation Male Middle Aged P450 Patients Pharmacogenomics Pharmacology Polymorphism Polymorphism, Single Nucleotide Single-nucleotide polymorphism SNP Statistical analysis Substrates Tacrolimus Tacrolimus - therapeutic use Tissue Donors Transplantation Transplants & implants Treatment Outcome Young Adult |
| title | Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients |
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