Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response.
Oral anticoagulants of the coumarin type have an inconveniently narrow therapeutic window, making their use difficult. In Mexico, genetic variables that participate in the heterogeneity of the therapeutic response remain poorly investigated. With the focus on warfarin, extensive pharmacogenomic studies have been performed, including those on the CYP450 family and APOE. The objective of this study was to determine the contribution of CYP2C9, CYP2C19, and APOE polymorphisms to the variations in response to the doses of acenocoumarol, which is the main anticoagulant prescribed to the Mexican population. The polymerase chain reaction-restriction fragment length polymorphism method was applied to identify 2 and 3 of CYP2C9, 2 of CYP2C19, and APOE variants. The genetic distribution of every polymorphism tested showed high variability when compared with other populations worldwide. Our results showed statistical differences only in the CYP2C19 gene between the 1 1 and 1 2 groups, with effective acenocoumarol doses of 2.56 ± 1.34 mg/day vs 1.35 ± 0.84 mg/day (P = 0.005), respectively. Multiple regression analysis, including patient age and both the CYP2C9 and CYP2C19 genes, showed that these variables explained more than 20% of the dose variations. This is the first report in Mexico searching for the relationship between CYP450 and APOE polymorphisms and the dose requirements of acenocoumarol. Our results suggest that, in the Mexican population, CYP2C19 is more involved in acenocoumarol metabolism than CYP2C9 and APOE. Besides considering the age factor, pharmacogenetic testing for CYP2C19 2 before initiating acenocoumarol treatment could lead to a safer anticoagulation therapy in Mexican patients.
Unidad de Genética, Centro de Microscopía Electrónica, Escuela de Ciencias de la Salud, Universidad de Oriente, Ciudad Bolívar, Bolívar, Venezuela.
J A
JA
Nastasi-Catanese
J R
JR
Padilla-Gutiérrez
Y
Y
Valle
F
F
Ortega-Gutiérrez
M P
MP
Gallegos-Arreola
L E
LE
Figuera
D000074:Acenocoumarol / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D000925:Anticoagulants; D001057:Apolipoproteins E; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000074:Acenocoumarol