Predicted expression of genes involved in the thiopurine metabolic pathway and azathioprine discontinuation due to myelotoxicity

Abstract

TPMT and NUDT15 variants explain less than 25% of azathioprine‐associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed Least Absolute Shrinkage and Selection Operator (LASSO) regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1 . Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.11–4.19, p = 0.024). Results remained significant after adjusting for a propensity score, including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data (HR = 2.11, 95% CI = 1.08–4.13, p = 0.030). We validated the results in a cohort ( N = 517 non‐White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR = 2.00, (95% CI = 1.09–3.65, p = 0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity.

Temporary Like Achilles: Pre‐emptive germline pharmacogenetic testing

“…7 In certain situations, it is neither necessary nor feasible to conduct randomized controlled trials (RCTs) because of ethical reasons, such as for pre-emptive testing for HLA-B*5701, dihydropyrimidine dehydrogenase (DPYD) or thiopurine S-methyltransferase (TPMT) variant alleles prior to treatment with abacavir, 5-fluorouracil (or prodrugs) or azathioprine. 8,9 Additionally, we acknowledge the RCTs, where pre-emptive PGx have been demonstrated to improve surrogate markers of clinical efficacy, secondary clinical endpoints or appear clinically meaningful in stratified analyses. For the most part though, guidelines are based on our understanding of pharmacokinetics, pharmacodynamic and variations in genes that affect drug metabolism enzymes or transporters.…”