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.

去铁酮（Deferiprone）作为一种铁螯合剂，可在β地中海贫血（β-thalassemia）患者中引发异质性药物不良反应（adverse drug reactions, ADRs），提示药物遗传学因素在其中发挥作用。为弥补现有药物遗传学数据的不足，本研究纳入相关临床与个体特征，探讨了介导去铁酮代谢的核心酶——尿苷二磷酸葡萄糖醛酸转移酶1A6（UGT1A6）的4种常见变异体与特定药物不良反应发生风险的关联。本研究纳入178名接受去铁酮治疗的伊朗重型β地中海贫血（β-thalassemia major）患者，构建回顾性队列进行分析。本研究依据临床指南定义药物不良反应，涵盖关节痛、胃肠道（gastrointestinal, GI）并发症、中性粒细胞减少症及肝酶升高，并通过医疗记录予以确认，辅以调查问卷补充信息。研究人员对4种UGT1A6多态性进行了基因分型，并采用并发症特异性分析框架及双倍型-单倍型（diplotype-haplotype）分析方法评估关联，同时校正了10项人口统计学、临床及治疗相关变量。整体药物不良反应发生率与单个单核苷酸多态性（single nucleotide polymorphisms, SNPs）无显著关联。分层分析结果显示，AA-GC双倍型（rs2070959–rs1105879）与关节痛风险降低相关（比值比[odds ratio, OR]=0.28，p=0.022）；而GC-AC双倍型则与胃肠道并发症风险升高相关（OR=5.48，p=0.007），且与中性粒细胞减少症存在接近显著的关联。女性性别仅与胃肠道并发症风险升高相关（p=0.002）。特定UGT1A6双倍型及性别与不同类型去铁酮相关药物不良反应存在特异性关联。采用并发症特异性的药物遗传学分析策略，可加深对去铁酮相关药物不良反应的认知。