单倍型结构定义了常见的二氢嘧啶脱氢酶（DPYD）基因变异c.85T>C（rs1801265）和c.496A>G（rs2297595）对二氢嘧啶脱氢酶活性的影响：对5-氟尿嘧啶毒性的启示。
Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: Implication for 5-fluorouracil toxicity.
作者信息
Hamzic Seid, Schärer Dominic, Offer Steven M, Meulendijks Didier, Nakas Christos, Diasio Robert B, Fontana Stefano, Wehrli Marc, Schürch Stefan, Amstutz Ursula, Largiadèr Carlo R
机构信息
Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, INO-F, Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
出版信息
Br J Clin Pharmacol. 2021 Aug;87(8):3234-3243. doi: 10.1111/bcp.14742. Epub 2021 Mar 30.
AIMS
The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy.
METHODS
Plasma dihydrouracil/uracil (UH /U) ratios were measured as a population marker for DPD activity in a total of 1382 subjects from 4 independent studies. Genotype and haplotype correlations with UH /U ratios were assessed.
RESULTS
Significantly lower UH /U ratios (p < 2 × 10 ) were observed in carriers of the 4 well-studied 5-FU toxicity risk variants with mean differences (MD) of -43.7% for DPYD c.1905 + 1G > A (rs3918290), -46.0% for DPYD c.1679T > G (rs55886062), -37.1%, for DPYD c.2846A > T (rs67376798), and -13.2% for DPYD c.1129-5923C > G (rs75017182). An additional variant, DPYD c.496A > G (rs2297595), was also associated with lower UH /U ratios (P < .0001, MD: -12.6%). A haplotype analysis was performed for variants in linkage disequilibrium with c.496A > G, which consisted of the common variant c.85T > C (rs1801265) and the risk variant c.1129-5923C > G. Both haplotypes carrying c.496A > G were associated with decreased UH /U ratios (H3, P = .003, MD: -9.6%; H5, P = .002, MD: -16.9%). A haplotype carrying only the variant c.85T > C (H2) was associated with elevated ratios (P = .004, MD: +8.6%).
CONCLUSIONS
Based on our data, DPYD-c.496A > G is a strong candidate risk allele for 5-FU toxicity. Our data suggest that DPYD-c.85T > C might be protective; however, the deleterious impacts of the linked alleles c.496A > G and c.1129-5923C > G likely limit this effect in patients. The possible protective effect of c.85T > C and linkage disequilibrium with c.496A > G and c.1129-5923C > G may have hampered prior association studies and should be considered in future clinical studies.
目的
本研究旨在识别损害二氢嘧啶脱氢酶（DPD）活性的风险变异体和单倍型，因此，这些是对5-氟尿嘧啶（5-FU）化疗产生严重毒性的候选风险变异体。
方法
在来自4项独立研究的总共1382名受试者中，测量血浆二氢尿嘧啶/尿嘧啶（UH/U）比值作为DPD活性的群体标志物。评估基因型和单倍型与UH/U比值的相关性。
结果
在4个经过充分研究的5-FU毒性风险变异体的携带者中观察到显著较低的UH/U比值（p<2×10），DPYD c.1905+1G>A（rs3918290）的平均差异（MD）为-43.7%，DPYD c.1679T>G（rs55886062）为-46.0%，DPYD c.2846A>T（rs67376798）为-37.1%，DPYD c.1129-5923C>G（rs75017182）为-13.2%。另一个变异体DPYD c.496A>G（rs2297595）也与较低的UH/U比值相关（P<.0001，MD：-12.6%）。对与c.496A>G处于连锁不平衡的变异体进行了单倍型分析，其由常见变异体c.85T>C（rs1801265）和风险变异体c.1129-5923C>G组成。携带c.496A>G的两种单倍型均与UH/U比值降低相关（H3，P=.003，MD：-9.6%；H5，P=.002，MD：-16.9%）。仅携带变异体c.85T>C（H2）的单倍型与比值升高相关（P=.004，MD：+8.6%）。
结论
基于我们的数据，DPYD-c.496A>G是5-FU毒性的一个强有力的候选风险等位基因。我们的数据表明DPYD-c.85T>C可能具有保护作用；然而，连锁等位基因c.496A>G和c.1129-5923C>G的有害影响可能会限制其在患者中的这种作用。c.85T>C的可能保护作用以及与c.496A>G和c.1129-5923C>G的连锁不平衡可能阻碍了先前的关联研究，应在未来的临床研究中予以考虑。
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