Gil-Rodriguez Almudena, Recarey-Rama Sheila, Fernández Montes Ana, Rodríguez-Viyuela Ana, Barros Francisco, Carracedo Angel, Maroñas Olalla
Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain.
Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Int J Mol Sci. 2025 Aug 22;26(17):8136. doi: 10.3390/ijms26178136.
Fluoropyrimidine derivatives can cause severe toxicity in patients with DPD deficiency. Regulatory agencies, such as the European Medicines Agency (EMA), recommend pre-emptive genotyping of the HapB3 haplotype, along with other variants. Historically, the two main HapB3 variants, the benign c.1236G>A and the pathogenic c.1129-5923C>G, have been assumed to be in complete linkage disequilibrium. Recent findings contradict this assumption, questioning the reliability of the HapB3 analysis through c.1236G>A, which could directly impact patient safety. The aim of this study is to assess the linkage disequilibrium between the c.1236G>A and c.1129-5923C>G variants, with the ultimate goal of revising genotyping guidelines. A total of 46 patients already heterozygous for the c.1236G>A variant have been carefully reviewed for the c.1129-5923C>G variant. From the 46 patients analyzed, 45 maintain complete linkage disequilibrium between both variants. However, there is one patient where this linkage disequilibrium is not complete, being heterozygous for c.1236G>A and homozygous for c.1129-5923C>G. These findings challenge the validity of c.1236G>A as a surrogate marker for pathogenic variant c.1129-5923C>G. This article highlights the need for a review of the recommendations of the EMA and suggests laboratories to analyze both variants, or at least the pathogenic one, to ensure accurate therapeutic decisions.
氟嘧啶衍生物可导致二氢嘧啶脱氢酶（DPD）缺乏的患者出现严重毒性。欧洲药品管理局（EMA）等监管机构建议对HapB3单倍型以及其他变体进行预先基因分型。从历史上看，HapB3的两个主要变体，良性的c.1236G>A和致病性的c.1129-5923C>G，被认为处于完全连锁不平衡状态。最近的研究结果与这一假设相矛盾，质疑通过c.1236G>A进行HapB3分析的可靠性，这可能直接影响患者安全。本研究的目的是评估c.1236G>A和c.1129-5923C>G变体之间的连锁不平衡，最终目标是修订基因分型指南。对46名已经是c.1236G>A变体杂合子的患者进行了仔细检查，以确定其c.1129-5923C>G变体情况。在分析的46名患者中，45名患者的两个变体之间保持完全连锁不平衡。然而，有一名患者的这种连锁不平衡并不完全，该患者为c.1236G>A杂合子和c.1129-5923C>G纯合子。这些发现挑战了c.1236G>A作为致病性变体c.1129-5923C>G替代标志物的有效性。本文强调了审查EMA建议的必要性，并建议实验室分析这两个变体，或至少分析致病性变体，以确保做出准确的治疗决策。
