Comprehensive overview of the global pharmacogenetic and functional variability in NUDT15

Thiopurine medications are widely used for the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. However, thiopurine-induced hemotoxicity occurs in up to 30% of patients, which causes substantial morbidity and limits therapeutic success. These adverse effects are associated with genetic variation in TPMT and NUDT15, which encode key enzymes involved in thiopurine metabolism. While the global distribution of TPMT variability has been extensively studied, less is known about the ethnogeographic variability of NUDT15, and no meta-analysis of available population frequencies has been reported. In this study, we aggregated genetic data from 150 studies and repositories comprising genotypes from a total of 1,401,592 individuals across 55 countries. We further synthesize the available clinical evidence for functional effects of NUDT15*5 and NUDT15*6, which are currently considered as variants with indeterminate functional effects. This synthesis indicates that both alleles significantly increase thiopurine adverse event risk. We aggregate the genetic information to spectra of functional variability to generate the first global maps of NUDT15 metabolizer phenotypes. We observe a graded distribution of NUDT15 deficiency, peaking in East Asia (46% of all individuals exhibit reduced NUDT15 activity) and declining across Central Asia (13.6%), Middle Eastern populations (3.8%) and Europe (2.1%). NUDT15 deficiency is furthermore prevalent on the Western coast of South and Central America but absent in Africa. Overall, our results provide a valuable resource for population-specific NUDT15 allele and metabolizer phenotype distributions, which can guide thiopurine risk assessment on a global scale.