Zhang J E, Klein Kathrin, Jorgensen Andrea L, Francis Ben, Alfirevic Ana, Bourgeois Stephane, Deloukas Panagiotis, Zanger Ulrich M, Pirmohamed Munir
Wolfson Centre for Personalized Medicine, Department of Molecular and Clinical Pharmacology, The University of LiverpoolLiverpool, United Kingdom.
Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgart, Germany.
Front Pharmacol. 2017 May 31;8:323. doi: 10.3389/fphar.2017.00323. eCollection 2017.
Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. is part of the gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the gene cluster on expression of the individual genes and warfarin response. mRNA levels of the gene cluster were quantified in human liver samples ( = 149) obtained from a well-characterized liver bank and fine mapping of the gene cluster encompassing , , and was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients ( = 711) was also analyzed for genetic variations across the gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between genes were explored using publicly available data repositories. We found that SNPs in , , and were associated with mRNA expression in the gene cluster. In particular, rs2108622 was associated with increased expression while rs1060467 was associated with decreased expression. Interestingly, these and SNPs showed similar effects with warfarin stable dose where rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, = 0.017), an effect opposite to that previously reported with (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, rs1799853, rs1057910, and rs9923231 improved warfarin dose variability only by 0.5-0.7% with an improvement in dose prediction accuracy of ∼1-2%. Although there is complex regulation across the gene cluster, the opposing effects between the two SNPs in the gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.
细胞色素P450（CYP）4F2是一种维生素K氧化酶，其编码基因中的遗传多态性会影响华法林的稳定剂量需求以及达到治疗性国际标准化比值（INR）的时间。CYP4F2是基因簇的一部分，该基因簇具有高度多态性且表现出高度连锁不平衡，因此难以确定因果变异。我们的目的是研究CYP4F2基因簇中的遗传变异性对各个CYP4F2基因表达及华法林反应的影响。在从一个特征明确的肝脏库获取的人类肝脏样本（n = 149）中对CYP4F2基因簇的mRNA水平进行了定量，并对包含CYP4F2、CYP4F11和CYP4F3的CYP4F2基因簇进行了精细定位。还分析了来自华法林治疗患者前瞻性队列（n = 711）的全基因组关联研究（GWAS）数据，以了解CYP4F2基因簇中的遗传变异。此外，利用公开可用的数据存储库探索了人类肝脏组织中的单核苷酸多态性（SNP）-基因表达以及CYP4F2基因之间的相互作用。我们发现，CYP4F2、CYP4F11和CYP4F3中的SNP与CYP4F2基因簇中的mRNA表达相关。特别是，CYP4F2 rs2108622与CYP4F2表达增加相关，而CYP4F11 rs1060467与CYP4F11表达降低相关。有趣的是，这些CYP4F11和CYP4F2 SNP对华法林稳定剂量的影响相似，其中CYP4F11 rs1060467与每日华法林剂量需求降低相关（约1 mg/天，P = 0.017），这一效应与先前报道的CYP4F2（rs2108622）相反。然而，将这些SNP中的一个或两个纳入由年龄、体重指数（BMI）、性别、基线凝血因子II水平、CYP2C9 rs1799853、VKORC1 rs1057910和F2 rs9923231组成的药物遗传学算法中，仅使华法林剂量变异性提高了0.5 - 0.7%，剂量预测准确性提高了约1 - 2%。尽管CYP4F2基因簇存在复杂的调控，但该基因簇中两个SNP之间的相反效应似乎相互抵消，它们对华法林剂量需求的影响在临床上不太可能具有显著意义。
