Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements

Cadamuro, Janne; Dieplinger, Benjamin; Felder, Thomas K.; Kedenko, Igor; Mueller, Thomas; Haltmayer, Meinhard; Patsch, Wolfgang; Oberkofler, Hannes

doi:10.1007/s00228-009-0768-7

Cited by 40 publications

(37 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The allele frequency was A (49%) and G (51%). This differed from frequencies reported in the HapMap CEU population, 10 (table 1, P <0.0001) but resembled other subpopulations of subjects from other studies with underlying cardiovascular disease conditions, 16,17 although ethnicity differed in these studies compared to the study cohort. The study cohort showed deviation from Hardy-Weinberg equilibrium (P = 0.035), while the HapMap CEU does not (P = 0.49, see table 2).…”

Section: Gene Frequenciescontrasting

confidence: 77%

“…In addition, because CALU is associated with >500 SNPs, some of which are in linkage disequilibrium with CALU SNP 1043550, a role for calumenin cannot be discounted based on studies of other SNPs in other populations where frequency distributions for the various SNPs were seen to vary with race and ethnicity A study in a German-Austrian population reported a statistically significant association between two CALU SNPs (rs2290228 C>T and rs2307040 G>A) in one individual who was homozygous T/T and G/G, respectively, and a substantially higher anticoagulation requirement (P = 0.0197). 10 However, they were unable to confirm an interaction with VKORC1 1173C>T and A29809G (rs 1043550) in their population. These SNPS do not appear to be in linkage disequilibrium with the SNP rs1043550 examined in the current study.…”

Section: Discussionmentioning

confidence: 90%

“…Applying a multiplex SNP approach and univariate analysis to examine 10 Whereas the two Spanish cohorts of acenocoumarol-exposed subjects exhibit nearly identical genotype frequency distribution, distributions between the Marshfield warfarin cohort and HapMap CEU population are significantly different (P=0.035).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies suggested that calumenin may contribute to variability in warfarin or acenocoumarol therapeutic dosing requirements, and observation of dosing outliers. [8][9][10] The present study, undertaken in a previously modeled warfarin cohort at Marshfield Clinic, sought to validate putative lower therapeutic warfarin dosing requirements among individuals encoding the wild type allele of the CALU SNP rs1043550 (A29809G), as had previously been reported for CALU SNPs examined in other phenotypically and genotypically modeled Caucasian cohorts.…”

mentioning

confidence: 90%

See 3 more Smart Citations

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

Glurich

Berg

Burmester

2013

Clinical Medicine & Research

View full text Add to dashboard Cite

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.

show abstract

Section: Gene Frequenciescontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

See 2 more Smart Citations

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

Glurich

Berg

Burmester

2013

Clinical Medicine & Research

View full text Add to dashboard Cite

show abstract

“…The most common complication of this OAC is bleeding, with major bleeding events occurring in 1%-3% of patients annually. Because of the narrow therapeutic range of this drug, many patients experience bleeding of variable severity or recurrent thrombotic events [1][2][3][4][5]. Monitoring of international normalized ratio (INR) and dose adjustments are frequently required during OAC therapy and are influenced by changes in concomitant medications, diet, alcohol consumption, acute illness, liver disease, and unknown factors [6].…”

Section: Introductionmentioning

confidence: 99%

Interaction between Levothyroxine and Phenprocoumon: a case report

2014

View full text Add to dashboard Cite

AbstractSeveral case reports have associated the combined use of thyroid drugs and oral anticoagulants, like coumarin, with overanticoagulation. However, this effect has never been described for phenprocoumon, a coumarin derivate that is widely prescribed in continental European countries and in Latin America. We describe a 62-year-old female who had an unexpectedly labile anticoagulation profile when levothyroxine (Puran T4®) was added to her drug therapy regimen, which included phenprocoumon (Marcoumar®). This resulted in an elevated international normalized ratio (INR) that was unrecordable and bleeding (macroscopic hematuria) that required hospitalization and treatment with vitamin K. The patient had been taking phenprocoumon for almost ten years for systemic embolism prophylaxis because of her history of mechanical bileaflet mitral valve prosthesis. One month before the events described, the patient was prescribed sodium levothyroxine (50 mcg daily) to treat hypothyroidism (TSH = 40 µU/mL; reference range, 0.40–4.0 µU/mL). Approximately 3 weeks prior to initiation of levothyroxine treatment, her INR was 2.8. A drug interaction was therefore suspected. The Horn Drug Interaction Probability Scale (DIPS) indicated a probable interaction between oral phenprocoumon and levothyroxine in this case. Clinicians should be aware that levothyroxine may interact with oral phenprocoumon, resulting in overanticoagulation.

show abstract