Genetic causes of resistance to vitamin K antagonists in Polish patients: a novel p.Ile123Met mutation in VKORC1 gene.
Blood Coagul Fibrinolysis
; 29(5): 429-434, 2018 Jul.
Article
em En
| MEDLINE
| ID: mdl-29794812
ABSTRACT
Mutations in the genes encoding vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) largely contribute to the inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Up to 50% of the dosage variability can be explained by genetic polymorphisms in these genes. We sought to identify the mutations responsible for VKA resistance in a series of Polish patients. Of the 607 patients treated with VKA, 35 (6%) individuals with the VKA resistance defined as a daily dose of acenocoumarol more than 8âmg (nâ=â15, 43%) or warfarin more than 10âmg (nâ=â20, 57%) were selected for further mutational analysis using Sanger sequencing (VKORC1) or real-time PCR genotyping (CYP2C9). The indications for anticoagulant treatment were venous thromboembolism (nâ=â28, 80%), atrial fibrillation (nâ=â6, 17%), or artificial heart valve (nâ=â1, 3%). Patients taking medication interfering with VKA were ineligible. Almost all of VKA-resistant patients (nâ=â34, 97%) possessed at least one VKORC1*3 (nâ=â29, 83%) or VKORC1*4 (nâ=â15, 43%) haplotypes. In a 70-year-old man atrial fibrillation patient on the daily acenocoumarol dose of 16âmg, a novel p.Ile123Met (c.369C>G) VKORC1 mutation was found. In-silico analysis showed that the p.Ile123Met can functionally underlie the acenocoumarol resistance, presumably by altering VKA binding. To our knowledge this is the first cohort of Polish patients resistant to VKA evaluated for the causal genetic background. We found one new detrimental mutation underlying VKA resistance. Our study highlights a key role of unidentified environmental factors in VKA resistance in daily clinical practice.
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Base de dados:
MEDLINE
Assunto principal:
Vitamina K
/
Vitamina K Epóxido Redutases
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Citocromo P-450 CYP2C9
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article