Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Pharmacogenet Genomics. 2011 Jan;21(1):26-34. doi: 10.1097/FPC.0b013e32834154fb.
Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role.
To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS.
We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage.
Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10⁻²². Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele.
Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene. CYP2C9 and CYP4F2 were of modest relevance.
华法林和醋硝香豆素的全基因组关联研究表明，个体间剂量差异主要与 VKORC1 中的单核苷酸多态性（SNP）相关，而 CYP2C9 和 CYP4F2 则有较小程度的相关。对于苯丙香豆素的剂量，编码 CYP3A4 和载脂蛋白 E 的基因可能发挥作用。
评估 VKORC1、CYP2C9、CYP4F2、CYP3A4 和载脂蛋白 E 内常见遗传变异与苯丙香豆素维持剂量之间的关系，并通过全基因组关联研究（GWAS）发现新的信号。
我们从接受苯丙香豆素治疗的鹿特丹研究中选择了所有参与者。对于每个 SNP，我们检测了上述基因型与年龄、性别、体重指数和目标 INR 调整后的苯丙香豆素维持剂量之间的关联。
在我们的研究人群（N=244）中，VKORC1、CYP2C9 和 CYP4F2 基因型共同解释了 46%的苯丙香豆素维持剂量的变异。每个额外的 VKORC1 变异等位基因使苯丙香豆素维持剂量减少 4.8 毫克/周（P<0.0001），每个额外的 CYP2C9 变异等位基因减少 2.2 毫克/周（P=0.002）。每个 CYP4F2 的额外变异等位基因使苯丙香豆素剂量增加 1.5 毫克/周（P=0.022）。CYP3A41*B 和载脂蛋白 E 的变异等位基因与苯丙香豆素剂量无关联。全基因组显著相关的 SNP 均与 VKORC1 活性相关。与 VKORC1 相互关联且与 VKORC1 内 SNP 相关的两个 SNP 最为相关：rs10871454（Syntaxin 4A [STX4A]）和 rs11150604（ZNF646），每个 SNP 的 P 值均为 2.1×10⁻²²。每个变异等位基因每周使苯丙香豆素维持剂量减少 4.9 毫克。
与华法林和醋硝香豆素的早期发现类似，苯丙香豆素的维持剂量取决于 VKORC1 基因中的多态性。CYP2C9 和 CYP4F2 有一定的相关性。
