Predicted expression of genes involved in the thiopurine metabolic pathway and azathioprine discontinuation due to myelotoxicity |
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| Authors: | Laura L. Daniel,Alyson L. Dickson,Jacy T. Zanussi,Tyne W. Miller‐ Fleming,Peter S. Straub,Wei‐ Qi Wei,W. Dale Plummer,William D. Dupont,Ge Liu,Prathima Anandi,Tyler S. Reese,Kelly A. Birdwell,Vivian K. Kawai,Adriana M. Hung,Nancy J. Cox,QiPing Feng,C. Michael Stein,Cecilia P. Chung |
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| Affiliation: | 1. Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee, USA ; 2. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville Tennessee, USA ; 3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville Tennessee, USA ; 4. Tennessee Valley Healthcare System, Nashville Virginia, USA |
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| 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. Study Highlights - WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Azathioprine is an immunosuppressant that causes myelotoxicity in some people. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide azathioprine dosing recommendations based on TPMT and NUDT15 genotype; however, these genotypes explain only 25% of azathioprine‐induced myelotoxicity. - WHAT QUESTION DID THIS STUDY ADDRESS?
The aim of this study was to determine if a risk score composed of the genetically predicted expression of genes that encode proteins in the thiopurine pathway within the liver tissue would be associated with azathioprine discontinuation attributed to myelotoxicity. - WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This study showed that a risk score composed of genetically predicted risk expression of AOX1 and NME1 is associated with azathioprine discontinuation due to myelotoxicity. - HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
Having a risk score for discontinuation composed of the genetically predicted expression of NME1 and AOX1 could help discriminate patients at high risk of discontinuing azathioprine due to hematologic side effects in people who are normal TPMT and NUDT15 metabolizers. |
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