New genetic biomarkers predicting azathioprine blood concentrations in combination therapy with 5-aminosalicylic acid

PLoS One. 2014 Apr 24;9(4):e95080. doi: 10.1371/journal.pone.0095080. eCollection 2014.

Abstract

Background and aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Transport Systems / genetics*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Azathioprine / pharmacokinetics*
  • Azathioprine / therapeutic use
  • Cells, Cultured
  • Drug Therapy, Combination
  • Female
  • Genetic Association Studies
  • Genetic Markers
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Immunosuppressive Agents / therapeutic use
  • Inflammatory Bowel Diseases / blood*
  • Inflammatory Bowel Diseases / drug therapy
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Male
  • Mesalamine / therapeutic use*
  • Middle Aged
  • Polymorphism, Single Nucleotide

Substances

  • Amino Acid Transport Systems
  • Anti-Inflammatory Agents, Non-Steroidal
  • Genetic Markers
  • Immunosuppressive Agents
  • SLC38A9 protein, human
  • Mesalamine
  • Azathioprine

Grants and funding

This work was supported by a Grant-in-Aid for Challenging Exploratory Research to Yuji Naito (No. 08101559); a Grant-in-Aid for Scientific Research (C) to Kazuhiko Uchiyama (No. 24590665) from the Japan Society for the Promotion of Science; the City Area Program to Yuji Naito from the Ministry of Education, Culture, Sports, Science and Technology, Japan; and the Adaptable and Seamless Technology Transfer Program through target-driven R&D to Yuji Naito from the Japan Science and Technology Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.