口服抗凝剂导致弥漫性肺泡出血患者的 VKORC1 和 CYP2C9 等位基因变异。

Variant VKORC1 and CYP2C9 alleles in patients with diffuse alveolar hemorrhage caused by oral anticoagulants.

机构信息

Department of Clinical Chemistry, Maastricht University Medical Centre, Maastricht, the Netherlands.

出版信息

Mol Diagn Ther. 2010 Feb 1;14(1):23-30. doi: 10.1007/BF03256350.

DOI:10.1007/BF03256350

PMID:20121287

Abstract

BACKGROUND

Diffuse alveolar hemorrhage (DAH) is a life-threatening bleeding complication that can occur as a result of oral anticoagulation therapy.

OBJECTIVE

We hypothesized that in patients treated with coumarins, alveolar hemorrhage is associated with vitamin K epoxide reductase (VKORC1) and cytochrome P450 (CYP) 2C9 (CYP2C9) variant alleles. In addition, in the case of acenocoumarol use, CYP2C19 allelic variants also play a role.

METHODS

During a 7-year period, data on patients using coumarins with confirmed DAH were gathered. Of 173 confirmed DAH cases, 75 received oral anticoagulants, and 63 (84%) of these 75 patients were included because their DNA was available. For genotyping the CYP2C92 (430C>T), CYP2C93 (1075A>C), CYP2C192 (681G>A), CYP2C193 (636G>A), VKORC1 (-1639G>A), and VKORC1 (1173C>T) single nucleotide polymorphisms (SNPs), real-time PCRs were performed.

RESULTS

In 62 (98.4%) of 63 patients with DAH, variant alleles were found. In 51 (81.0%) of the 63 patients, VKORC1 allelic variants (20 homozygotes and 31 heterozygotes) were present. In 31 (49.2%) of the 63 DAH cases, CYP2C9 allelic variants (three homozygotes, 26 heterozygotes, and two compound heterozygotes) were observed, and in 20 (32.0%) of the 63 patients, variant alleles of both genes were observed.

CONCLUSION

Genotyping of four SNPs for VKORC1 and CYP2C9 polymorphisms is useful in predicting a high probability of the occurrence of DAH in patients receiving oral anticoagulants. Early and timely use of genotyping is recommended to prevent a fatal outcome and to provide safer and more individualized anticoagulant therapy.

摘要

背景

弥漫性肺泡出血 (DAH) 是一种危及生命的出血并发症，可能由口服抗凝治疗引起。

目的

我们假设在接受香豆素治疗的患者中，肺泡出血与维生素 K 环氧化物还原酶 (VKORC1) 和细胞色素 P450 (CYP) 2C9 (CYP2C9) 变体等位基因有关。此外，在使用 acenocoumarol 的情况下，CYP2C19 等位基因变体也起作用。

方法

在 7 年期间，收集了使用香豆素并确诊 DAH 的患者的数据。在 173 例确诊的 DAH 病例中，有 75 例接受了口服抗凝剂治疗，其中 63 例（84%）患者因 DNA 可用而被纳入研究。为了对 CYP2C92 (430C>T)、CYP2C93 (1075A>C)、CYP2C192 (681G>A)、CYP2C193 (636G>A)、VKORC1 (-1639G>A) 和 VKORC1 (1173C>T) 单核苷酸多态性 (SNP) 进行基因分型，我们进行了实时 PCR。

结果

在 63 例 DAH 患者中，有 62 例（98.4%）发现了变体等位基因。在 63 例患者中，有 51 例（81.0%）存在 VKORC1 等位基因变体（20 个纯合子和 31 个杂合子）。在 63 例 DAH 病例中，有 31 例（49.2%）存在 CYP2C9 等位基因变体（3 个纯合子、26 个杂合子和 2 个复合杂合子），在 63 例患者中，有 20 例（32.0%）存在两个基因的变体等位基因。