New genetic biomarkers predicting azathioprine blood concentrations in combination therapy with 5-aminosalicylic acid.
New genetic biomarkers predicting azathioprine blood concentrations in combination therapy with 5-aminosalicylic acid.
复制标题
DOI：
10.1371/journal.pone.0095080
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Itoh Y
中科院分区：
文献类型：
--
作者：
Uchiyama K;Takagi T;Iwamoto Y;Kondo N;Okayama T;Yoshida N;Kamada K;Katada K;Handa O;Ishikawa T;Yasuda H;Sakagami J;Konishi H;Yagi N;Naito Y;Itoh Y
硫唑嘌呤(AZA)广泛用于炎症性肠病(IBD)患者的治疗。硫代嘌呤S甲基转移酶(TPMT)催化氮杂环己烷的代谢，呈现遗传多态。也有报道称，5-氨基水杨酸(5-ASA)可抑制TPMT的活性，并且增加6-硫鸟苷(6-TGN，AZA的代谢物)的血药浓度会导致ADRs的数量增加。本研究检测了联合应用5-ASA时影响AZA药物代谢差异基因表达的单核苷酸多态(SNPs)。为了确定预测6-TGN血药浓度的遗传生物标记物，采用ExpressGenetic分析。快速基因分型分析能够通过分析药物诱导的HapMap淋巴细胞中早熟RNA的表达等位基因失衡(EAI)来检测关键的药物遗传SNPs。我们采集了38例使用AZA治疗的炎症性肠病患者的血液样本，并试图在临床样本中证实所获得的SNPs。通过快速基因分型分析，在被调查的HapMap淋巴细胞中发现了大量含有AZA/5-ASA诱导的EAI的SNP。分别对IBD患者血液样本中的SNPs进行分析。在这些SNP中，发现了几个尚未被AZA/5-ASA诱导的SNP。SLC38A9基因的SNPs与患者的6-TGN血药浓度有一定的相关性。基于这些结果，对患者的快速基因分型分析和基因分型似乎是确定对AZA/5-ASA的药物反应和不良反应的个体间差异的有用方法。本研究为优化AZA/5-ASA治疗IBD患者提供了有用的遗传生物标志物信息。
Azathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S-methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined. To identify genetic biomarkers for the prediction of 6-TGN blood concentration, ExpressGenotyping analysis was used. ExpressGenotyping analysis is able to detect critical pharmacogenetic SNPs by analyzing drug-induced expression allelic imbalance (EAI) of premature RNA in HapMap lymphocytes. We collected blood samples on 38 patients with inflammatory bowel disease treated with AZA and corroboration of the obtained SNPs was attempted in clinical samples. A large number of SNPs with AZA/5-ASA-induced EAI within the investigated HapMap lymphocytes was identified by ExpressGenotyping analysis. The respective SNPs were analyzed in IBD patients' blood samples. Among these SNPs, several that have not yet been described to be induced by AZA/5-ASA were found. SNPs within SLC38A9 showed a particular correlation with patients' 6-TGN blood concentrations. Based on these results, ExpressGenotyping analysis and genotyping of patients appears to be a useful way to identify inter-individual differences in drug responses and ADRs to AZA/5-ASA. This study provides helpful information on genetic biomarkers for optimized AZA/5-ASA treatment of IBD patients.
登录
查看更多内容
影响因子：
12.6
作者：
Cuffari, Carmen;Dassopoulos, Themistocles;Bayless, Theodore M.
通讯作者：
Bayless, Theodore M.
影响因子：
30.8
作者：
Knight, JC;Keating, BJ;Kwiatkowski, DP
通讯作者：
Kwiatkowski, DP
影响因子：
3.3
作者：
González-González, IM;Cubelos, B;Zafra, F
通讯作者：
Zafra, F
影响因子：
3.4
作者：
Haglund, Sofie;Taipalensuu, Jan;Almer, Sven
通讯作者：
Almer, Sven
影响因子：
2.5
作者：
Derijks, LJJ;Gilissen, LPL;Hooymans, PM
通讯作者：
Hooymans, PM