Does CALU SNP rs1043550 Contribute Variability to Therapeutic Warfarin Dosing Requirements?

Abstract

Objectives: 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. Setting: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.Methods: 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.Results: 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. Conclusions: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.

Warfarin Dose Model for the Prediction of Stable Maintenance Dose in Indian Patients

“…[1][2][3][4][5] Genetic variations in cytochrome P450-4F2 (CYP4F2), g-glutamyl carboxylase (GGCX), epoxide hydrolase 1 (EPHX1), calumenin (Calu), factor IX (F9), and factor VII (F7) gene also have shown subsidiary association with warfarin response. [6][7][8][9][10][11][12] Other nongenetic factors including ethnicity, age, body mass index, weight, and gender are also known to have a minor role in warfarin sensitivity. [13][14][15][16][17][18][19] Based on pharmacogenetics, clinical, and demographic factors, population-based warfarin pharmacogenomic algorithms have been generated for various ethnic groups.…”

Hypermethylation of brain natriuretic peptide gene is associated with the risk of rheumatic heart disease

“…Fluctuations of individual warfarin dosages can influence the severity of RHD in genetic factors. At present, researches showed usage of warfarin on stable doses on RHD causing CYP2C9 , CYP4F2 and VKORC1 gene polymorphisms in the Chinese Han population [31,32]. In our study, the long-term anticoagulant therapy of warfarin in RHD patients after valve replacement changed expression levels of BNP DNA methylation sites in the field of apparent genetics.…”

Frequency of Common VKORC1 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

“…[59][60][61] A number of other studies have also shown such deviation from HWE without affecting the results. 6,12,[62][63][64] As far as the status of LD among these SNPs is concerned, a recent Italian study also reported nonexistence of LD between VKORC1 1173C>T and VKORC1-1639G>A genotypes. 10 A number of studies have revealed that different VKORC1 SNPs group differently to form haplotypes because of diverse LD relationship in different populations and their distribution varies in different populations.…”