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Article(id=1218551264951063370, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551212711006298, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2018-0050, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1515686400000, receivedDateStr=2018-01-12, revisedDate=1520784000000, revisedDateStr=2018-03-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1768454861151, onlineDateStr=2026-01-15, pubDate=1526054400000, pubDateStr=2018-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768454861151, onlineIssueDateStr=2026-01-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768454861151, creator=13701087609, updateTime=1768454861151, updator=13701087609, issue=Issue{id=1218551212711006298, tenantId=1146029695717560320, journalId=1189982191388893191, year='2018', volume='53', issue='5', pageStart='659', pageEnd='832', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768454848696, creator=13701087609, updateTime=1768457015494, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218560300975046777, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551212711006298, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218560300975046778, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551212711006298, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=765, endPage=770, ext={EN=ArticleExt(id=1218551265601180569, articleId=1218551264951063370, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Associations of IMPDH1 polymorphisms with pharmacodynamics of mycophenolic acid in renal transplant patients, columnId=1218263842866516365, journalTitle=Acta Pharmaceutica Sinica, columnName=ORIGINAL ARTICLES·Pharmacology, runingTitle=null, highlight=null, articleAbstract=

The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy (mycophenolic acid + tacrolimus + prednisone). The Agena MassARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid (MPA) and its main metabolite mycophenolic acid glucuronide (MPAG) was detected by high performance liquid chromatography (HPLC). The correlation between IMPDH1 gene polymorphism (rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation (P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation (P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.

, correspAuthors=Jia-li LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2018 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Shou-ning ZHOU, Li QIN, Si LIU, Long-shan LIU, Yi-shu ZHANG, Huan-xi ZHANG, Chang-xi WANG, Min HUANG, Jia-li LI), CN=ArticleExt(id=1218551266427457538, articleId=1218551264951063370, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性分析, columnId=1218263843034288529, journalTitle=药学学报, columnName=研究论文·药理学, runingTitle=null, highlight=null, articleAbstract=

探讨IMPDH1基因多态性对肾移植患者麦考酚酸类药物药效学的影响。纳入315例肾移植术后进行三联免疫疗法（麦考酚酸类药物+他克莫司+泼尼松）的患者。采用Agena MassARRAY®方法检测患者IMPDH1基因型。通过高效液相色谱法检测术后稳定期患者麦考酚酸（MPA）及其主要代谢物麦考酚酸葡萄糖苷酸（MPAG）的血浆药物浓度。应用SPSS 21.0软件对IMPDH1基因多态性（rs10954183、rs12536006、rs13242340、rs2278293、rs2288549）与肾移植患者排斥、术后感染等指标的相关性进行分析。结果显示，IMPDH1 rs2288549 AG型是肾移植患者术后出现急性排斥反应的危险因素（OR=6.629，P < 0.05）；IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素（OR=2.812，P < 0.05）。以上研究表明，IMPDH1 rs2288549是肾移植患者术后出现急性排斥反应的影响因素，IMPDH1 rs2278293是肾移植患者术后出现感染的影响因素，上述SNP可作为参考优化临床用药方案，提高疗效，降低不良反应的发生率。

, correspAuthors=李嘉丽, authorNote=null, correspAuthorsNote=
* 李嘉丽, Tel:86-20-39943034-806, E-mail:
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Ethical Dilemma of Organ Shortage and Its Strategy in China (我国供体器官短缺的伦理困境及其对策)[D]. Nanchang: Jiangxi Normal University, 2009., articleTitle=null, refAbstract=null), Reference(id=1218970787076297584, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Qi L, Li JL, Liu XM, et al. Associations of VDR polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients[J]. 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Acta Pharm Sin (药学学报), 2009, 44:1397-1401., articleTitle=null, refAbstract=null), Reference(id=1218970787369898901, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract16633.shtml, language=null, rfNumber=[4], rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Huang JW. The Dssociation of Dosage Form and Pharmacogenetic Factors with Drug Exposure and Adverse Reaction of Mycophenolic Acid in Renal Transplant Recipients (剂型和药动学遗传因素与肾移植患者霉酚酸暴露量及不良反应相关性研究)[D]. Guangzhou: Sun Yat-sen University, 2011., articleTitle=null, refAbstract=null), Reference(id=1218970787495728029, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Loparev VN, Cartas MA, Monken CE, et al. An efficient and simple method of DNA extraction from whole blood and cell lines to identify infectious agents[J]. J Virol Methods, 1991, 34:105-112., articleTitle=null, refAbstract=null), Reference(id=1218970787663500205, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Cao W, Xiao H, Lai X, et al. Genetic variations in the mycophenolate mofetil target enzyme are associated with acute GVHD risk after related and unrelated hematopoietic cell transplantation[J]. Biol Blood Marrow Transplant, 2012, 18:273-279., articleTitle=null, refAbstract=null), Reference(id=1218970787789329345, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang J, Yang JW, Zeevi A, et al. IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients[J]. Clin Pharmacol Ther, 2008, 83:711-717., articleTitle=null, refAbstract=null), Reference(id=1218970787889992656, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Kagaya H, Miura M, Saito M, et al. Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation[J]. Basic Clin Pharmacol Toxicol, 2010, 107:631-636., articleTitle=null, refAbstract=null), Reference(id=1218970788007433179, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Zukowska A, Kotfis K, Kaczmarczyk M, et al. Impact of graft infection on long-term survival after kidney transplant[J]. Transplant Proc, 2014, 46:2752-2754., articleTitle=null, refAbstract=null), Reference(id=1218970788137456619, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Picard N, Marquet P. The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation[J]. Expert Opin Drug Metab Toxicol, 2011, 7:731-743., articleTitle=null, refAbstract=null), Reference(id=1218970788296840183, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Hronova K, Sima M, Svetlik S, et al. Pharmacogenetics and immunosuppressive drugs[J]. 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Item Value
Number of patients 315
Sex (male/female) 204/111
Age (years) 35.95 ± 11.96
Weight/kg 56.70 ± 12.93
Cr/μmol·L-1 139.59 ± 93.51
CLcr/mL·min-1 57.51 ± 20.12
ALB/g·L-1 41.95 ± 4.29
ALT/U·L-1 27.25 ± 24.86
AST/U·L-1 20.53 ± 10.78
Donor type (1/2/3/4/5) 100/51/47/19/98
Cold ischemia time/h 13.80 ± 7.19
HLA matching type (0/1) 73/11
Delayed graft function (No/Yes) 299/16
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Clinical and information of the 315 patients studied. Cr: Creatinine; CLcr: Creatinine clearance; ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HLA: Human leukocyte antigen

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Item Value
Number of patients 315
Sex (male/female) 204/111
Age (years) 35.95 ± 11.96
Weight/kg 56.70 ± 12.93
Cr/μmol·L-1 139.59 ± 93.51
CLcr/mL·min-1 57.51 ± 20.12
ALB/g·L-1 41.95 ± 4.29
ALT/U·L-1 27.25 ± 24.86
AST/U·L-1 20.53 ± 10.78
Donor type (1/2/3/4/5) 100/51/47/19/98
Cold ischemia time/h 13.80 ± 7.19
HLA matching type (0/1) 73/11
Delayed graft function (No/Yes) 299/16
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Item Negative Positive Incidence rate/%
Acute rejection 271 24 8.14
Second set acute rejection 291 4 1.36
Infection 261 54a 17.14
Pulmonary infection 268 27 9.15
Upper respiratory tract infection 108 15 12.20
Urinary tract infection 283 12 4.07
Gastrointestinal infection 118 5 4.07
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Clinical information of pharmacodynamic index. aThe total number of infections includes the combined infection

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Item Negative Positive Incidence rate/%
Acute rejection 271 24 8.14
Second set acute rejection 291 4 1.36
Infection 261 54a 17.14
Pulmonary infection 268 27 9.15
Upper respiratory tract infection 108 15 12.20
Urinary tract infection 283 12 4.07
Gastrointestinal infection 118 5 4.07
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SNP Genotype n Frequency
/%		 Allele Allele frequency
/%		 H-W P-value
rs10954183 CC 77 36.67 C 58.81 0.21
CT 93 44.29 T 41.19
TT 40 19.05
rs12536006 AA 39 18.40 A 40.33 0.20
AG 93 43.87 G 59.67
GG 80 37.74
rs13242340 AA 40 19.05 A 41.19 0.21
AC 93 44.29 C 58.81
CC 77 36.67
rs2278293 CC 64 30.48 C 53.57 0.30
CT 97 46.19 T 46.43
TT 49 23.33
rs2288549 AG 19 11.11 A 5.56 0.44
GG 152 88.89 G 94.44
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Frequency distribution of IMPDH1 polymorphisms

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SNP Genotype n Frequency
/%		 Allele Allele frequency
/%		 H-W P-value
rs10954183 CC 77 36.67 C 58.81 0.21
CT 93 44.29 T 41.19
TT 40 19.05
rs12536006 AA 39 18.40 A 40.33 0.20
AG 93 43.87 G 59.67
GG 80 37.74
rs13242340 AA 40 19.05 A 41.19 0.21
AC 93 44.29 C 58.81
CC 77 36.67
rs2278293 CC 64 30.48 C 53.57 0.30
CT 97 46.19 T 46.43
TT 49 23.33
rs2288549 AG 19 11.11 A 5.56 0.44
GG 152 88.89 G 94.44
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Group AUC P-value
Acute rejection Second set acute rejection Infection Pulmonary infection Upper respiratory tract infection Urinary tract infection Gastrointestinal infection
MMF+MPS MPA 0.365 0.057 0.371 0.918 0.047a 0.795 0.850
MPAG 0.312 0.243 0.492 0.594 0.542 0.309 0.984
MMF MPA 0.183 0.706 0.587 0.689 0.304 0.695 0.774
MPAG 0.659 0.212 0.115 0.125 0.617 0.050 0.817
MPS MPA 0.896 0.027a 0.416 0.543 0.066 0.486 0.893
MPAG 0.654 0.456 0.660 0.981 0.954 0.815 0.857
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Association of pharmacokinetic factors and pharmacodynamic index. MMF: Mycophenolate mofetil; MPS: Mycophenolate sodium; MPA: Mycophenolic acid; MPAG: Mycophenolic acid glucuronide. aP < 0.05 (The difference remained significant before the Bonferroni correction, but none of the difference remained significant after the Bonferroni correction)

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Group AUC P-value
Acute rejection Second set acute rejection Infection Pulmonary infection Upper respiratory tract infection Urinary tract infection Gastrointestinal infection
MMF+MPS MPA 0.365 0.057 0.371 0.918 0.047a 0.795 0.850
MPAG 0.312 0.243 0.492 0.594 0.542 0.309 0.984
MMF MPA 0.183 0.706 0.587 0.689 0.304 0.695 0.774
MPAG 0.659 0.212 0.115 0.125 0.617 0.050 0.817
MPS MPA 0.896 0.027a 0.416 0.543 0.066 0.486 0.893
MPAG 0.654 0.456 0.660 0.981 0.954 0.815 0.857
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Pharmacodynamic index SNP Genotype Acute rejection Total P-value
Negative Positive
Acute rejection rs2288549 AG 13 6 19 P=0.014a
GG 121 15 136
Total 134 21 155
Infection rs2278293 CC+TT 102 11 113 P=0.042a
CT 78 19 97
Total 180 30 210
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Correlation between IMPDH1 gene polymorphism and pharmacodynamic indexes. aP < 0.05 (The difference remained significant before the Bonferroni correction, but none of the difference remained significant after the Bonferroni correction)

, figureFileSmall=null, figureFileBig=null, tableContent=
Pharmacodynamic index SNP Genotype Acute rejection Total P-value
Negative Positive
Acute rejection rs2288549 AG 13 6 19 P=0.014a
GG 121 15 136
Total 134 21 155
Infection rs2278293 CC+TT 102 11 113 P=0.042a
CT 78 19 97
Total 180 30 210
), ArticleFig(id=1218970784723292926, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Pharmacodynamic index Independent factor Coefficient OR 95% CI P-value Nagelkerke R square Model P-value
Acute rejection IMPDH1 rs2288549 1.649 5.200 (1.081, 25.014) 0.040 0.121 0.044
Constant -7.000 0.001 0.001
Infection IMPDH1 rs2278293 1.226 3.409 (1.101, 10.557) 0.033 0.113 0.029
Constant -2.143 0.117 0.021
), ArticleFig(id=1218970786061275916, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551264951063370, language=CN, label=Table 6, caption=

Analysis of factors affecting pharmacodynamic indexes. OR: Odds ratio; CI: Confidence interval

, figureFileSmall=null, figureFileBig=null, tableContent=
Pharmacodynamic index Independent factor Coefficient OR 95% CI P-value Nagelkerke R square Model P-value
Acute rejection IMPDH1 rs2288549 1.649 5.200 (1.081, 25.014) 0.040 0.121 0.044
Constant -7.000 0.001 0.001
Infection IMPDH1 rs2278293 1.226 3.409 (1.101, 10.557) 0.033 0.113 0.029
Constant -2.143 0.117 0.021
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IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性分析
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周守宁 1 , 覃利 2 , 刘思 1 , 刘龙山 3 , 张亦舒 1 , 张桓熙 3 , 王长希 3 , 黄民 1 , 李嘉丽 1, *
药学学报 | 研究论文·药理学 2018,53(5): 765-770
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药学学报 | 研究论文·药理学 2018, 53(5): 765-770
IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性分析
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周守宁1, 覃利2, 刘思1, 刘龙山3, 张亦舒1, 张桓熙3, 王长希3, 黄民1, 李嘉丽1, *
作者信息
  • 1.中山大学药学院临床药理研究所, 广东 广州 510080
  • 2.中山大学附属第六医院药学部, 广东 广州 510655
  • 3.中山大学附属第一医院器官移植中心, 广东 广州 510080

通讯作者:

* 李嘉丽, Tel:86-20-39943034-806, E-mail:
Associations of IMPDH1 polymorphisms with pharmacodynamics of mycophenolic acid in renal transplant patients
Shou-ning ZHOU1, Li QIN2, Si LIU1, Long-shan LIU3, Yi-shu ZHANG1, Huan-xi ZHANG3, Chang-xi WANG3, Min HUANG1, Jia-li LI1, *
Affiliations
  • 1. Institute of Clinical Pharmacology, School of Pharmacy, Sun Yat-sen University, Guangzhou 510080, China
  • 2. Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
  • 3. Organ Transplant Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
出版时间: 2018-05-12 doi: 10.16438/j.0513-4870.2018-0050
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摘要
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探讨IMPDH1基因多态性对肾移植患者麦考酚酸类药物药效学的影响。纳入315例肾移植术后进行三联免疫疗法（麦考酚酸类药物+他克莫司+泼尼松）的患者。采用Agena MassARRAY®方法检测患者IMPDH1基因型。通过高效液相色谱法检测术后稳定期患者麦考酚酸（MPA）及其主要代谢物麦考酚酸葡萄糖苷酸（MPAG）的血浆药物浓度。应用SPSS 21.0软件对IMPDH1基因多态性（rs10954183、rs12536006、rs13242340、rs2278293、rs2288549）与肾移植患者排斥、术后感染等指标的相关性进行分析。结果显示，IMPDH1 rs2288549 AG型是肾移植患者术后出现急性排斥反应的危险因素（OR=6.629，P < 0.05）；IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素（OR=2.812，P < 0.05）。以上研究表明，IMPDH1 rs2288549是肾移植患者术后出现急性排斥反应的影响因素，IMPDH1 rs2278293是肾移植患者术后出现感染的影响因素，上述SNP可作为参考优化临床用药方案，提高疗效，降低不良反应的发生率。

肾移植  /  麦考酚酸  /  药效学  /  急性排斥  /  感染  /  药物基因组学

The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy (mycophenolic acid + tacrolimus + prednisone). The Agena MassARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid (MPA) and its main metabolite mycophenolic acid glucuronide (MPAG) was detected by high performance liquid chromatography (HPLC). The correlation between IMPDH1 gene polymorphism (rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation (P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation (P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.

renal transplantation  /  mycophenolic acid  /  pharmacodynamics  /  acute rejection  /  infection  /  pharmacogenomics
周守宁, 覃利, 刘思, 刘龙山, 张亦舒, 张桓熙, 王长希, 黄民, 李嘉丽. IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性分析. 药学学报, 2018 , 53 (5) : 765 -770 . DOI: 10.16438/j.0513-4870.2018-0050
Shou-ning ZHOU, Li QIN, Si LIU, Long-shan LIU, Yi-shu ZHANG, Huan-xi ZHANG, Chang-xi WANG, Min HUANG, Jia-li LI. Associations of IMPDH1 polymorphisms with pharmacodynamics of mycophenolic acid in renal transplant patients[J]. Acta Pharmaceutica Sinica, 2018 , 53 (5) : 765 -770 . DOI: 10.16438/j.0513-4870.2018-0050
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据统计, 我国每年约有6 000例新增肾移植患者, 肾移植数实际累计超过2万例次, 居世界第二[1]。成功的肾移植可以为终末期肾病患者提供有效的治疗。然而, 肾移植术后急性排斥反应、感染等因素都可能导致肾移植治疗的失败, 影响患者的生存质量。制定合理的免疫抑制剂用药方案是提高肾移植成功率的关键。
麦考酚酸类药物(MPA)是临床常用的免疫抑制剂, 是肾移植术后常规三联免疫疗法(麦考酚酸类药物+钙调蛋白酶抑制剂+皮质醇类激素)的关键用药。该类药物主要通过介导非竞争性抑制淋巴细胞的次黄嘌呤核苷酸脱氢酶(IMPDH), 阻止淋巴细胞的增殖, 达到免疫抑制的目的。然而, 麦考酚酸类药物的个体化用药面临着许多问题。不同个体在使用麦考酚酸治疗后的反应存在较大差异, 无法有效控制不良反应的发生。遗传因素是药物出现药动学和药效学个体差异的重要因素, 阐明该因素在药物治疗中的作用将有助于推动个体化合理用药。IMPDH1是MPA的主要作用位点, 广泛存在于体内的组织细胞, 可能与MPA的疗效存在关联性。
本研究拟探讨IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性, 以急性排斥指标作为主要疗效指标, 各类感染作为不良反应指标进行研究, 为临床个体化合理用药提供帮助。
材料与方法
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药品和仪器  吗替麦考酚酯片(骁悉, MMF, 瑞士罗氏制药有限公司); 麦考酚钠肠溶片(米芙, MPS, 瑞士诺华制药有限公司); 他克莫司(普乐可复, 爱尔兰安斯泰来制药集团); 泼尼松(广东华南药业集团有限公司); 注射用甲泼尼龙琥珀酸钠(甲强龙, 美国辉瑞制药有限公司); 麦考酚酸(纯度≥98.90%, 批号: 028K2572, 美国西格玛奥德里奇公司); 麦考酚酸葡萄糖苷酸(MPAG, 纯度≥99%, 批号: 0810006, 英国分析服务国际有限公司); 萘普生(纯度≥99%, 批号: 038K5158, 英国阿法埃莎化学有限公司)。高效液相色谱检测系统、高效液相色谱数据采集处理工作站(美国Waters公司); Agena MassARRAY分析仪(美国Agena公司); ABI PCR仪(美国ABI公司)。
病例选择  分析2008年4月~2017年8月于中山大学附属第一医院行肾移植术的315例肾移植患者。本研究经中山大学附属第一医院伦理委员会批准。上述患者均签署知情同意书。入选标准: ①首次接受肾移植术的患者; ②术后进行三联免疫疗法的患者:麦考酚酸类药物+他克莫司+泼尼松; ③术后3年内接受随访获悉疗效及不良反应发生情况的患者。排除标准: ①联合器官移植及二次移植的患者; ②乙肝表面抗原阳性者及肝功能异常的患者; ③入选前或者观察期间发生严重外科并发症的患者; ④观察期间依从性差, 无法按时服药的患者; ⑤观察期间进行过血液透析治疗的患者; ⑥观察期间临床情况和病历资料不全者。
免疫抑制方案[2, 3]  本研究所有患者均于肾移植术后采用三联免疫疗法(麦考酚酸类药物+他克莫司+泼尼松)。麦考酚酸类药物包括吗替麦考酚酯片(MMF)和麦考酚钠肠溶片(MPS), 其中MMF的剂量为0.5~0.75 g, 每12 h服用一次; MPS的剂量为0.36~0.72 g, 每12 h服用一次。他克莫司初始给药剂量为0.05~0.075 mg·kg-1, 每12 h服用一次, 根据谷浓度监测值调整剂量, 将谷浓度控制在5~15 ng·mL-1。术后3天内静脉滴注甲强龙, 每天500 mg; 术后第4天改为口服泼尼松, 每天30 mg, 术后第3个月剂量减至10~15 mg。
采样方案  在本研究中, 根据上述的病例选择标准, 采集入组患者的血样。对于服用吗替麦考酚酯片(MMF)的患者主要基于有限取样法[4], 考察用药后0.5、1.5、4和9 h共4个时间点的MPA血药浓度, 并计算MPA和MPAG的AUC0-12 h。对于服用麦考酚钠肠溶片(MPS)的患者, 考察用药前和用药后1、2.5、4、5、6、7、8、9、10.5和12 h共11个时间点的MPA血药浓度, 并计算MPA和MPAG的AUC0-12 h。此外, 本研究留取患者的外周血用于提取对应患者的DNA, 用以进行后续的基因型检测。
MPA血药浓度的测定[4]  采用本实验室前期建立的高效液相色谱法(HPLC)同时检测血浆MPA及MPAG的浓度。MPA的定量线性范围为0.1~50 mg·L-1, MPAG的定量线性范围为0.5~200 mg·L-1。血药浓度的计算由HPLC系统自带的Empower高效液相色谱数据采集处理工作站完成并保存原始记录。MPA浓度检测的时间为术后8天至术后3年内发生排斥反应或者术后感染后。
外周血DNA的提取  参考优化Loparev等[5]的提取方法。
基因型检测[2]  采用基于基质辅助激光解吸电离飞行时间质谱(MALDI-TOF MS)的Agena MassARRAY® iPLEX基因分型技术进行检测:该基因检测技术主要是将DNA样本进行PCR扩增, 加入设计好的SNP序列特异延伸引物, 在SNP位点上延伸特定的1个碱基。接着将样品与芯片基质共结晶, 使用瞬时纳秒强激光激发。核酸分子解吸附转变为亚稳态离子, 在非电场漂移区内按照其质荷比率实现分离。上述亚稳态离子在真空小管中飞行到达检测器, 离子质量越小, 越快到达, 从而判定不同的碱基类型, 实现对SNP的检测。
信息采集  收集满足入选标准患者的一般临床资料[性别、年龄、身高、体重、肌酐(Cr)、肌酐清除率(CLcr)、白蛋白(ALB)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、肾脏来源、冷缺血时间、人白细胞抗原(HLA)配型、肾功能延迟恢复(DGF)]、用药情况以及其对应3年内通过复诊和随访等获悉的药效学资料(急性排斥、二次急性排斥、总感染、肺部感染、上呼吸道感染、尿路感染和胃肠道感染)。
数据统计  应用SPSS 21.0软件对数据进行统计分析。计算各位点的基因型频率和等位基因频率, 通过卡方检验验证SNP基因型分布是否符合Hardy-Weinberg平衡。采用5种遗传模型(显性模型、共显性模型、隐性模型、超显性模型和附加模型)对基因型数据进行统计分析。采用Kruskal-Wallis非参数检验和卡方检验分析临床因素、药效学指标与相关基因多态性的相关性, 同时对结果进行Bonferroni校正; 采用logistics回归分析影响药效学指标的因素, 纳入临床资料、基因型、药物浓度进行分析。本研究运用了显性模型、隐性模型、超显性模型、共显性模型和附加模型对基因型数据进行分析。在显性模型中, 设定等位基因A为风险因素, 将基因型AA和Aa合并与基因型aa进行比较分析; 在隐形模型中, 设定等位基因a为风险因素, 将基因型Aa和aa合并与基因型AA进行比较分析; 在超显性模型中, 设定Aa具有显性遗传效应, 将基因型AA和aa合并与基因型Aa进行比较分析; 在共显性模型中, 单独对AA、Aa和aa进行分析; 在附加模型中, 对等位基因A和a分别进行统计分析。
结果
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1 一般资料
本研究315例肾移植患者的一般资料及药动学资料见表 1。其中肾脏来源包括活体移植、脑死亡器官捐献移植、心脏死亡器官捐献移植、脑心双死亡器官捐献移植、其他类型(表中分别以1~5表示); HLA配型以HLA错配数作为分类依据, HLA错配数 < 4以0表示, HLA错配数≥4以1表示。
2 药动学资料
本研究共纳入315例肾移植患者, 其中服用MMF的患者为142例, 服用MPS的患者为173例。在服用MMF的患者中, MPA和MPAG的AUC均值分别为52.64 ± 23.83和929.80 ± 737.12 mg·h·L-1; 在服用MPS的患者中, MPA和MPAG的AUC均值分别为57.34 ± 34.21和1268.86 ± 785.04 mg·h·L-1。
3 药效学资料
本研究纳入的药效学指标包括疗效指标和不良反应指标。所有患者的不良反应均参照《药物不良反应监察指南》, 由临床合作医师结合患者的症状、体征及相关检验结果进行判断并记录。本研究纳入的药效学资料包括急性排斥、二次急性排斥、感染(包括肺部感染、上呼吸道感染、尿路感染、胃肠道感染), 具体资料见表 2。
4 基因型频率与等位基因频率分布情况
本研究共纳入5个IMPDH1 SNP: rs10954183、rs12536006、rs13242340、rs2278293和rs2288549。上述位点的基因频率分布、等位基因分布频率及Hardy-Weinberg平衡检验结果见表 3。rs10954183、rs12536006、rs13242340、rs2278293和rs2288549均符合Hardy-Weinberg平衡(P > 0.05)。在本研究中, 5个SNP的基因型检出率(call rate)均大于95%。
5 药动学因素与药效学指标的相关性分析
本研究人群分为MMF + MPS组、MMF组和MPS组, 结果见表 4。在MMF + MPS组人群中, MPA的AUC值与上呼吸道感染的发生存在一定的相关性(P < 0.05), 经Bonferroni校正后该差异不具有统计学差异; 在MPS组人群中, AUC-MPA与二次急性排斥的发生存在一定的相关性(P < 0.05), 经Bonferroni校正后该差异不具有统计学差异。
6 IMPDH1基因多态性与药效学指标的相关性分析
通过卡方检验分析IMPDH1基因多态性与药效学指标的相关性(表 5): IMPDH1 rs2288549与肾移植患者术后出现急性排斥反应具有相关性(P < 0.05), AG型患者急性排斥的发生率高于GG型患者, 经Bonferroni校正后该差异不具有统计学差异; 在超显性模型中, IMPDH1 rs2278293与肾移植患者术后感染具有相关性(P < 0.05), CC+TT型患者感染的发生率低于CT型患者, 经Bonferroni校正后该差异不具有统计学差异。
采用logistics回归分析影响药效学指标的因素(表 6): ①在显性模型中, IMPDH1 rs2288549 AG型是肾移植患者术后出现急性排斥反应的危险因素(OR = 5.200, P < 0.05), OR值的95%置信区间为1.081~25.014, 该因素可以解释12.1%急性排斥的发生; ②在超显性模型中, IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素(OR = 3.409, P < 0.05), OR值的95%置信区间为1.101~10.557, 该因素可以解释11.3%感染的发生。
讨论
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麦考酚酸类药物是肾移植术后三联免疫疗法的关键部分, 该类药物的个体化合理用药, 有助于建立更加合理的个体化给药方案, 从而达到更好的疗效, 减少不良反应的发生。本研究以遗传因素作为切入点, 探讨IMPDH1基因多态性对肾移植患者麦考酚酸类药物药效学指标的影响, 为肾移植术后患者用药方案调整和预后评估提供参考。IMPDH1是MPA的主要作用靶点, 于体内不同组织细胞广泛表达, 对细胞内嘌呤的合成具有重要作用[6]。目前, 有关IMPDH1基因多态性与患者服用麦考酚酸类药物后疗效及不良反应的关系也引起关注。本研究主要通过IMPDH1基因遗传多态性研究文献、NCBI dbSNP数据库、麦考酚酸相关研究文献筛选拟纳入研究的SNP[6-9], 且对相关SNP频率分布进行初步研究, 剔除罕见突变、不满足Hardy-Weinberg平衡的SNP。综合上述的数据搜集和已有研究结果, 本研究选择纳入了上述5个IMPDH1的SNP进行分析研究。
MPA作为临床常用的抗排药, 患者在治疗过程中是否发生排斥是重要的疗效指标, 已有多项研究对IMPDH1基因多态性与移植术后多种排斥反应的相关性进行探讨。Wang等[7]发现IMPDH1 rs2278293与术后1年发生BPAR相关; Kagaya等[8]发现IMPDH1 rs2278293 AA型是急性排斥的保护因素; Cao等[6]提出IMPDH1 rs2278293与异基因造血干细胞移植患者发生急性移植物抗宿主病(aGVHD)相关。然而本研究并未发现该位点与术后3年发生的急性排斥相关, 推测可能与研究人群、病种及药效学指标的差异相关, 后续研究需要进一步扩大样本量, 同时补充功能学的研究进一步深入探讨。本研究发现IMPDH1 rs2288549 AG型是肾移植患者术后出现急性排斥反应的危险因素, 尚未有相关报道研究该位点与不良反应具有相关性。该位点在HapMap-HCB数据库的突变率为6.98%, 位于7号染色体内含子区域, 推测其频率较低的突变型等位基因A对IMPDH1非翻译区的表达产生了影响, 影响了IMPDH1酶的表达, 使得携带A等位基因的个体对药物敏感性较低, 对细胞内嘌呤的合成的影响较小, 从而增加了排斥反应的风险。
控制肾移植患者术后感染将有效提高肾移植患者生存率[9]。本研究发现IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素。针对不良反应资料, 本研究在统计中纳入了肺部感染、上呼吸道感染、尿路感染、胃肠道感染等不同感染相关资料, 分别分析了IMPDH1相关基因型与总感染数及各类感染的相关性。目前尚无IMPDH1与移植术后感染具有相关性的研究报道。本次研究发现IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素。该位点在HapMap-HCB数据库的突变率为45.56%, 位于7号染色体内含子区域, 野生型与突变型的频率分布接近, 推测该位点通过影响IMPDH1非翻译区的表达, 携带CT型的患者IMPDH1酶活性较强, 导致机体对药物敏感性比预想中的高, 从而导致了感染的发生。本次研究还发现MPA浓度与肾移植患者术后出现感染具有相关性, 但未能纳入logistics模型, 推测遗传因素导致药物靶点IMPDH1活性个体差异对不良反应的发生可能具有更重要的影响。同样地, 本次研究还分析了他克莫司浓度与肾移植患者术后出现感染的相关性, 然而该因素未能纳入模型。由于感染的发生还受到药物治疗方案、手术、环境等多种因素的影响, 研究过程中可能存在多种干扰, 后期研究需要纳入更多的因素进行分析, 补充相关的基础研究。
此外, 本研究的样本量偏小, 尤其是发生排斥的患者仅24例, 可能会导致诸如logistics回归分析中OR的95%置信区间较宽等问题, 后续需要进一步扩大样本量, 对本研究结果进行验证。
随着药物基因组学的发展, 为了更准确地分析不同个体间的差异, 探讨药物疗效的内在因素, 更好地实现个体化精准医疗, 针对遗传因素的研究成为了当前的研究热点, 越来越多的研究聚焦于遗传因素与药物用药方案优化的研究[10, 11]。本研究以IMPDH1基因多态性为研究重点, 结合考虑患者的一般临床数据、相关药物浓度, 探讨影响患者药效学指标的遗传因素。本研究发现IMPDH1相关基因型与相关疗效和不良反应具有相关性, 可作为参考指标, 优化临床用药方案, 提高用药疗效, 降低不良反应的发生率。
基金
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  • 国家重点研发计划项目(2017YFC0909303)
  • 国家重点研发计划项目(2016YFC0905001)
  • 国家自然科学基金资助项目(81320108027)
  • 广东省重点实验室建设项目(2011A060901014)
文献
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doi: 10.16438/j.0513-4870.2018-0050
  • 接收时间：2018-01-12
  • 首发时间：2026-01-15
  • 出版时间：2018-05-12
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  • 收稿日期：2018-01-12
  • 修回日期：2018-03-12
基金
国家重点研发计划项目(2017YFC0909303)
国家重点研发计划项目(2016YFC0905001)
国家自然科学基金资助项目(81320108027)
广东省重点实验室建设项目(2011A060901014)
作者信息
    1.中山大学药学院临床药理研究所, 广东 广州 510080
    2.中山大学附属第六医院药学部, 广东 广州 510655
    3.中山大学附属第一医院器官移植中心, 广东 广州 510080

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* 李嘉丽, Tel:86-20-39943034-806, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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