The objective of this study was to determine whether, in African‐American patients, additional vitamin K oxidoreductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), CYP4F2, or ...apolipoprotein E (APOE) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9*2 and *3 alleles and the VKORC1 −1639G>A genotype. In a cohort of 226 African‐American patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30–47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28–40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35–56) mg). The combination of CYP2C9 alleles, VKORC1 −1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9*5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1, CYP4F2, or APOE polymorphism contributed to the variance. The inclusion of additional CYP2C9 variants may improve the predictive ability of warfarin dosing algorithms for African Americans.
Clinical Pharmacology & Therapeutics (2010) 87 4, 459–464. doi:10.1038/clpt.2009.223
Metoprolol is a selective β‐1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of ...CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty‐one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response‐guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P < 0.0001), with poor and intermediate metabolizers showing greater reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not determinants of variability in metoprolol response or tolerability.
Clinical Pharmacology & Therapeutics (2014); 96 2, 175–181. doi:10.1038/clpt.2014.62
Abstract Bisphosphonate induced osteonecrosis of the jaw (BONJ) is a complication in patients taking bisphosphonate (BP) that affects their quality of life and compliance. In this cohort study, ...patients with multiple myeloma (MM) on intravenous BP therapy were enrolled over 1 year. Demographic and clinical data and genotyping of 10 single nucleotide polymorphisms (SNPs) from seven candidate genes associated with drug or bone metabolism were determined. Of the 78 patients enrolled, 12 had BONJ. The median time to developing BONJ was 28 months. Univariate and multivariate analysis revealed a significant association between BONJ and smoking ( p = 0.048) and type of BP treatment ( p = 0.03). A trend for higher odds for BONJ was found for SNPs in five genes: COL1A1 (rs1800012), RANK (rs12458117), MMP2 (rs243865), OPG (rs2073618) and OPN (rs11730582). Considering all five SNPs together, patients with genotype scores ≥5 had a BONJ event rate of 57%; those with scores <5 had a rate of 10%. The adjusted odds ratio was 11.2 (95% confidence interval of 1.8–69.9; p value 0.0097). Smoking, type of BP and combined genotype score of COL1A1 , RANK , MMP2 , OPG and OPN were significantly associated with BONJ in MM patients undergoing BP therapy.
Although there is increasing evidence to support the implementation of pharmacogenetics in certain clinical scenarios, the adoption of this approach has been limited. The advent of preemptive and ...inexpensive testing of critical pharmacogenetic variants may overcome barriers to adoption. We describe the design of a customized array built for the personalized‐medicine programs of the University of Florida and Stanford University. We selected key variants for the array using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB), and we included variants in drug metabolism and transporter genes along with other pharmacogenetically important variants.
Clinical Pharmacology & Therapeutics (2012); 92 4, 437–439. doi:10.1038/clpt.2012.125
Numerous studies have demonstrated that β1‐ and β2‐adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and β‐blocker responses in hypertension and heart failure. We ...evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol‐based vs. verapamil sustained‐release (SR)‐based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49‐Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68–7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06–35.8) but not atenolol (HR 2.31, 95% CI 0.82–6.55), suggesting a protective role for the β‐blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and β‐blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.
Clinical Pharmacology & Therapeutics (2008); 84, 6, 715–721 doi:10.1038/clpt.2008.139
Objective
Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide ...polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)‐induced elevations in UA and hyperuricaemia.
Methods
A genome‐wide association study of HCTZ‐induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add‐on therapy. Replicated regions were followed up through expression and pathway analysis.
Results
Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL−1 were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ‐induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the ‘top’ SNP from each gene region, was strongly associated with HCTZ‐induced UA elevations (P = 1.79 × 10−7) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs.
Conclusion
Several novel gene regions were associated with HCTZ‐induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).
The human carboxylesterase 1 (
CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the ...course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject's
CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260–299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate,
p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (
V
max
/
K
m
) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific
CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates.
Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains ...underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.
There is substantial variation in the dose of warfarin required to achieve therapeutic anticoagulation. In this study, mathematical models for warfarin dosage were constructed that used either ...clinical factors alone or clinical and genetic factors. The model incorporating genetic factors, when tested retrospectively with data from an international cohort, provided better estimates than a model that included only clinical factors.
Mathematical models for warfarin dosage were constructed that used either clinical factors alone or clinical and genetic factors. The model incorporating genetic factors provided better estimates than a model that included only clinical factors.
Warfarin is the most widely used oral anticoagulant agent worldwide; more than 30 million prescriptions were written for this drug in the United States in 2004.
1
The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of taking an incorrect dose can be catastrophic. Because incorrect doses contribute to a high rate of adverse effects, there is interest in developing improved strategies for determining the appropriate dose.
2
Clinical factors, demographic variables, and variations in two genes — cytochrome P450, family 2, subfamily C, polypeptide 9 (
CYP2C9
. . .
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.
Celotno besedilo
Dostopno za:
DOBA, EMUNI, GIS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK
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