Combining clinical and candidate gene data into a risk score for azathioprine-associated leukopenia in routine clinical practice

Pharmacogenomics J. 2020 Oct;20(5):736-745. doi: 10.1038/s41397-020-0163-4. Epub 2020 Feb 14.

Abstract

Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Azathioprine / adverse effects*
  • Databases, Genetic
  • Female
  • Genetic Association Studies
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Leukopenia / chemically induced
  • Leukopenia / diagnosis
  • Leukopenia / genetics*
  • Male
  • Methyltransferases / genetics*
  • Middle Aged
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Pilot Projects
  • Polymorphism, Single Nucleotide*
  • Proof of Concept Study
  • Risk Assessment
  • Risk Factors
  • Sex Factors

Substances

  • Immunosuppressive Agents
  • Methyltransferases
  • TPMT protein, human
  • Azathioprine