Subject(s)
Biomedical Research/organization & administration , Drug-Related Side Effects and Adverse Reactions/genetics , Evidence-Based Medicine/organization & administration , Interdisciplinary Communication , National Institutes of Health (U.S.)/organization & administration , Pharmacogenetics/organization & administration , Pharmacogenomic Variants/genetics , Animals , Biomedical Research/standards , Consensus , Cooperative Behavior , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/prevention & control , Evidence-Based Medicine/standards , Genotype , Humans , Pharmacogenetics/standards , Phenotype , Practice Guidelines as Topic , Risk Assessment , United StatesABSTRACT
Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8 ± 5.8, 7.2 ± 4.7, and 5.4 ± 4.6 days, P = 0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P = 0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population.
Subject(s)
Anticoagulants/administration & dosage , Pharmacogenetics , Warfarin/administration & dosage , Algorithms , Alleles , Anticoagulants/pharmacokinetics , Anticoagulants/therapeutic use , Cytochrome P-450 CYP2C9/genetics , Dose-Response Relationship, Drug , Endpoint Determination , Female , Genotype , Humans , Male , Middle Aged , Vitamin K Epoxide Reductases/genetics , Warfarin/pharmacokinetics , Warfarin/therapeutic useABSTRACT
A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide (HCTZ) in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and HCTZ response in an independent sample of 746 Caucasians and African-Americans randomized to HCTZ or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4 mmHg, P=0.0275; diastolic: 2.5 mmHg, P=0.0196) responses to HCTZ vs T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as HCTZ specific. Expression analyses in HCTZ-treated African-Americans showed differential pre-treatment leukocyte YEATS4 expression between rs7297610 genotype groups (P=0.024), and reduced post-treatment expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.
