Glurich Ingrid, Berg Richard L, Burmester James K
Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, USA.
Clin Med Res. 2013 Jun;11(2):73-9. doi: 10.3121/cmr.2013.1130. Epub 2013 May 8.
Calumenin, a molecular chaperone, exerts a regulatory effect on the vitamin K-dependent γ-carboxylation redox cycle that inhibits transfer of the reduced vitamin K from VKORC1, the pharmacological target of warfarin, to the γ-carboxylase. Because of its polymorphic structure and central role in the warfarin metabolic pathway, a contributory role for calumenin to warfarin dose variability has been posited. The current study sought to validate modulation of therapeutic dosing requirements by a single nucleotide polymorphisms (SNP) occurring in the calumenin gene (CALU) reported in previous studies. The CALU SNP was further modeled to detect interaction with SNPs occurring in VKORC1, CYP2C9, and CYP4F2 genes and characterize any additional contribution to variability in therapeutic warfarin dose requirement.
The study was undertaken in an established, well-characterized cohort of subjects treated with warfarin in the Anticoagulation Clinic of Marshfield Clinic in Marshfield, Wisconsin.
Subjects (N=491) previously genotyped for SNPS known to contribute variability to therapeutic warfarin dose requirement were genotyped for CALU SNP rs1043550, using TaqMan assays. Contribution of CALU SNP rs1043550 was modeled relative to other genotypic and phenotypic characteristics including gender, diagnosis, age, body surface area, underlying indication for warfarin, comorbidities, and pharmacological exposures. Interaction between SNPs impacting on warfarin dose requirements and calumenin SNPs was also modeled.
Small differences in warfarin dosing requirements detected among individuals encoding the mutant G allele in the calumenin SNP were not statistically or clinically significant relative to therapeutic warfarin dose requirement and did not independently contribute significantly to the warfarin dosing model. Interaction between calumenin and VKORC1 SNPs contributed only minor additional variability to that ascribed to the wild type VKORC1 genotype.
The impact of the CALU SNP on warfarin dose variability was minor and did not contribute significantly to therapeutic warfarin dose requirement in our study cohort. While no contribution was noted for the SNP examined in the present study, further examination of interaction between genetic elements contributing major impact on therapeutic warfarin dose requirements and genes exhibiting a lesser contribution is warranted.
钙连蛋白作为一种分子伴侣，对维生素K依赖的γ-羧化氧化还原循环发挥调节作用，该循环可抑制还原型维生素K从华法林的药理学靶点维生素K环氧化物还原酶（VKORC1）向γ-羧化酶的转移。由于其多态性结构以及在华法林代谢途径中的核心作用，有人提出钙连蛋白对华法林剂量变异性有促成作用。本研究旨在验证先前研究报道的钙连蛋白基因（CALU）中发生的单核苷酸多态性（SNP）对治疗剂量需求的调节作用。对CALU SNP进行进一步建模，以检测其与VKORC1、CYP2C9和CYP4F2基因中发生的SNP之间的相互作用，并确定其对治疗性华法林剂量需求变异性的任何额外影响。
本研究在威斯康星州马什菲尔德市马什菲尔德诊所抗凝门诊接受华法林治疗的一组既定且特征明确的受试者中进行。
使用TaqMan分析方法，对先前已针对已知会导致治疗性华法林剂量需求变异性的SNP进行基因分型的491名受试者进行CALU SNP rs1043550的基因分型。相对于其他基因型和表型特征，包括性别、诊断、年龄、体表面积、华法林的潜在适应证、合并症和药物暴露情况，对CALU SNP rs1043550的作用进行建模。还对影响华法林剂量需求的SNP与钙连蛋白SNP之间的相互作用进行建模。
在编码钙连蛋白SNP中突变G等位基因的个体中检测到的华法林剂量需求的微小差异，相对于治疗性华法林剂量需求而言，在统计学或临床上均无显著意义，并且对华法林剂量模型没有独立的显著贡献。钙连蛋白与VKORC1 SNP之间的相互作用仅对归因于野生型VKORC1基因型的变异性产生了微小的额外影响。
在我们的研究队列中，CALU SNP对华法林剂量变异性的影响较小，对治疗性华法林剂量需求没有显著贡献。虽然本研究中检测的SNP未显示出有影响，但有必要进一步研究对治疗性华法林剂量需求有主要影响的遗传因素与影响较小的基因之间的相互作用。
