Combining Clinical and Candidate Gene Data into a Risk Score for Azathioprine-Associated Leukopenia in Routine Clinical Practice

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 one, two, three and four, respectively. During the replication phase, models two and four (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 to TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.