Figure 2. Association of NUDT15 diplotype with MP tolerance during ALL therapy in Guatemala, Singapore, and Japan.

Patients were classified as “normal”, “intermediate”, or “low” NUDT15 activity on the basis of their diplotype at 4 coding variants (panels A, B, and C for the Guatemalan, Singaporean, and Japanese cohorts, respectively). MP dosage was adjusted during maintenance therapy to avoid host toxicities and tolerated MP dosage was defined as the average over at least 14 daily dosages after at least 9 weeks of maintenance therapy. Cases with TPMT variants (rs1800462, rs1800460, and rs1142345) were excluded from the analysis. P value was calculated by using linear regression test, after adjusting for co-variates when applicable. In panels A–C, each box includes data between 25^th and 75^th percentiles, with horizontal line indicating median. Similar association analyses were performed to compare tolerated MP dosage between normal and intermediate NUDT15 groups (P = 0.04, 0.00049, and 0.0033 for Panels A, B, and C, respectively). Meta-analysis combining test statistics from three cohorts indicated consistent association (Forest plot, Panel D, P = 4.45 × 10⁻⁸), with no significant heterogeneity across cohorts (P = 0.34). Allelic effect size indicates the change in MP dosage for every copy of the NUDT15 risk allele. The length of each horizontal line represents the range of 95% confidence interval of allelic effect size with the tick indicating median (gray boxes are proportional to weights of each cohort used in meta-analysis). Dashed vertical line denotes allelic effect size in the meta-analysis with the lateral tips of diamond representing 95% confidence interval.