Univ. Grenoble Alpes, Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, CHU Grenoble Alpes, Grenoble, France.
Department of Pharmacology, Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France.
Br J Clin Pharmacol. 2023 Aug;89(8):2446-2457. doi: 10.1111/bcp.15715. Epub 2023 Mar 30.
Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil [U], with U ≥ 16 μg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors.
Data from patients who underwent both phenotyping and genotyping were retrospectively collected. Complementary genetic analyses (genotyping of the variant c.557A>G and DPYD sequencing) were performed for patients with U ≥ 16 μg/L without any common variants. The characteristics of patients classified according to the congruence of the phenotyping and genotyping approaches were compared (Kruskal-Wallis test), and determinants of U levels were studied in the whole cohort (linear model).
Among the 712 included patients, phenotyping and genotyping were discordant for 12.5%, with 63 (8.8%) having U ≥ 16 μg/L in the absence of a common variant. Complementary genetic investigations marginally reduced the percentage of discrepancies to 12.1%: Among the nine additional identified variants, only the c.557A>G variant, carried by three patients, had been previously reported to be associated with DPD deficiency. Liver dysfunction could explain certain discordances, as ASAT, ALP, GGT and bilirubin levels were significantly elevated, with more frequent liver metastases in patients with U ≥ 16 μg/L and the absence of a DPYD variant. The impact of cytolysis was confirmed, as ASAT levels were independently associated with increased U (p < 0.001).
The frequent discordances between DPD phenotyping and genotyping approaches highlight the need to perform these two approaches to screen for all DPD deficiencies.
二氢嘧啶脱氢酶（DPD）缺乏症可通过表型（测量血浆尿嘧啶[U]，U≥16μg/L 定义为部分缺乏）和/或基因型（筛查最常见的四种 DPYD 变体）来检测。我们旨在确定表型和基因型方法之间存在差异的比例，并确定可能的解释因素。
回顾性收集接受表型和基因型检测的患者数据。对于 U≥16μg/L 且无任何常见变体的患者，进行补充基因分析（变体 c.557A>G 的基因分型和 DPYD 测序）。根据表型和基因型方法一致性对患者进行分类，并比较患者特征（Kruskal-Wallis 检验），并在整个队列中研究 U 水平的决定因素（线性模型）。
在 712 名纳入患者中，表型和基因型存在 12.5%的不一致性，其中 63 名（8.8%）在无常见变体的情况下 U≥16μg/L。补充基因研究将差异百分比略有降低至 12.1%：在另外鉴定的九个变体中，只有三个患者携带的 c.557A>G 变体之前与 DPD 缺乏有关。肝功能障碍可能解释了某些不一致性，因为 ASAT、ALP、GGT 和胆红素水平显著升高，U≥16μg/L 且无 DPYD 变体的患者肝转移更频繁。细胞溶解的影响得到了证实，因为 ASAT 水平与 U 的增加独立相关（p<0.001）。
DPD 表型和基因型方法之间经常存在不一致性，这强调需要进行这两种方法来筛查所有 DPD 缺乏症。
