Pharmacogenomic and Clinical Predictors of Deferasirox Response in Transfusion-Dependent Thalassemia Identified Using Whole-Genome Sequencing

Abstract

Deferasirox is a widely used oral iron chelator in patients with transfusion-dependent thalassemia, but considerable variability in treatment response remains a clinical challenge. This study applied whole-genome sequencing to investigate genetic predictors of deferasirox response in 88 Thai patients. This approach enabled comprehensive detection of both known and novel variants across eight key genes involved in deferasirox metabolism and transport. Two novel intronic variants in ABCC2 emerged as strong and clinically relevant predictors of treatment response. The homozygous TG deletion variant rs3047477 in ABCC2 (MAF 31.8%) was significantly associated with greater reductions in liver iron concentrations and increased iron excretion, whereas the rare variant rs188034361 was linked to poorer outcomes. Haplotype analysis identified a 69-kilobase linkage block comprising 12 tightly linked variants, grouped into distinct clusters. Clusters 3.4 and 4.4 were associated with greater reductions in serum ferritin, whereas clusters 2.2, 2.3, and 4.5 predicted suboptimal response. Two variants in UGT1A3 were found to have novel associations with deferasirox response. Specifically, the rs33979061 variant (MAF 6.8%) was associated with poorer treatment outcomes, whereas the rs540607993 variant (MAF 1.1%) predicted enhanced ferritin reduction. Previously reported associations involving UGT1A1 (*28, *6) and UGT1A3 (rs3806596) were also confirmed. Clinical factors, including baseline iron overload, transfusion intensity, body mass index, and age, also contributed to treatment variability. These findings support the implementation of pharmacogenetic profiling to guide personalized chelation strategies in patients with transfusion-dependent thalassemia. © 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.