UGT1A6 variants and deferiprone-induced ADRs: a complication-specific analysis in Iranian thalassemia patients

Deferiprone, an iron chelator, causes variable adverse drug reactions (ADRs) in β-thalassemia patients, suggesting a role for pharmacogenetic factors. To address the lack of comprehensive pharmacogenetic data, this study investigated the association between four common UGT1A6 variants - the primary enzyme metabolizing deferiprone - and the occurrence of specific ADRs, considering relevant clinical and personal characteristics.

A retrospective cohort of 178 Iranian β-thalassemia major patients on deferiprone was studied. ADRs - arthralgia, gastrointestinal (GI) complications, neutropenia, and liver enzyme elevations - were defined using clinical guidelines, confirmed by medical records, and supplemented by questionnaires. Four UGT1A6 polymorphisms were genotyped, and associations were evaluated using a complication-specific framework and diplotype - haplotype analyses, adjusting for ten demographic, clinical, and treatment variables.

Overall ADR incidence was not significantly associated with individual SNPs. Stratified analysis revealed that the AA - GC diplotype (rs2070959-rs1105879) was associated with reduced arthralgia risk (OR = 0.28, p = 0.022), whereas the GC - AC diplotype was linked to increased GI complication risk (OR = 5.48, p = 0.007) and showed a near-significant association with neutropenia. Female sex was associated only with increased GI complications (p = 0.002).

Specific UGT1A6 diplotypes and sex are differentially associated with distinct deferiprone-related ADRs. A complication-specific pharmacogenetic approach can improve understanding of deferiprone-related ADRs.