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.
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This work is supported by grant R01GM126535 R01GM109145, R35GM131770, and by the Rheumatology Research Foundation K-supplement and R01 bridge awards. PA was supported by grants T32AR059039 and T32GM007569. VKK was supported by NIH/NIGMS K23GM117395 and the National Arthritis Research Foundation—All Arthritis Grant Program Award. CPC was also supported by grant AR073764. The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu/index.html?sid=229. The funding sources had no role in the collection, analysis, or interpretation of data, writing of the paper, or decision to submit for publication.
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Anandi, P., Dickson, A.L., Feng, Q. et al. Combining clinical and candidate gene data into a risk score for azathioprine-associated leukopenia in routine clinical practice. Pharmacogenomics J (2020). https://doi.org/10.1038/s41397-020-0163-4