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1.  Adrenergic-pathway Gene Variants Influence β-Blocker-related Outcomes after Acute Coronary Syndrome in a Race-specific Manner 
Objective
Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for US healthcare. Genetic polymorphisms in the adrenergic pathway appear to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor-blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown.
Background
BB after ACS is a measure of quality care, but the effectiveness across racial groups, is less clear.
Methods
A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African Americans) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors.
Results
The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion (D) carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (HR 0.46; CI 0.21, 0.99; p=0.047; race-by-genotype interaction p= 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (HR for RG vs. GG =2.10; CI 1.14, 3.86; RR vs. GG =2.65; CI 1.38, 5.08; p=0.013; race-by-genotype interaction p=0.096).
Conclusions
Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasian and African Americans may illuminate opportunities to improve BB therapy in these groups.
doi:10.1016/j.jacc.2012.02.051
PMCID: PMC3678950  PMID: 22703928
2.  Genetics InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT): Rationale and Study Design 
The pharmacogenomics journal  2011;12(5):417-424.
The risk of venous thromboembolism (VTE) is higher after total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT) is a 2×2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) Does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) Is a lower target International Normalized Ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR ≥ 4, and death.
doi:10.1038/tpj.2011.18
PMCID: PMC3175019  PMID: 21606949
pharmacogenetics; warfarin; randomized controlled trial; dosing algorithm
3.  Pharmacogenetic Warfarin Dose Refinements Remain Significantly Influenced by Genetic Factors after One Week of Therapy 
Thrombosis and Haemostasis  2011;107(2):232-240.
Summary
Introduction
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Results
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
Conclusions
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
doi:10.1160/TH11-06-0388
PMCID: PMC3292349  PMID: 22186998
warfarin; VKORC1; CYP2C9; pharmacogenetic
4.  Gamma-glutamyl carboxylase and its influence on warfarin dose 
Thrombosis and haemostasis  2010;104(4):750-754.
Background
Via generation of vitamin K-dependent proteins, gamma-glutamyl carboxylase (GGCX) plays a critical role in the vitamin K cycle. Single nucleotide polymorphisms (SNPs) in GGCX, therefore, may affect dosing of the vitamin K antagonist, warfarin.
Methods
In a multi-centered, cross-sectional study of 985 patients prescribed warfarin therapy, we genotyped for two GGCX SNPs (rs11676382 and rs12714145) and quantified their relationship to therapeutic dose.
Results
GGCX rs11676382 was a significant (p=0.03) predictor of residual dosing error and was associated with a 6.1% reduction in warfarin dose (95% CI: 0.6%-11.4%) per G allele. The prevalence was 14.1% in our predominantly (78%) Caucasian cohort, but the overall contribution to dosing accuracy was modest (partial R2 = 0.2%). GGCX rs12714145 was not a significant predictor of therapeutic dose (p = 0.26).
Conclusions
GGCX rs11676382 is a statistically significant predictor of warfarin dose, but the clinical relevance is modest. Given the potentially low marginal cost of adding this SNP to existing genotyping platforms, we have modified our non-profit website (www.WarfarinDosing.org) to accommodate knowledge of this variant.
doi:10.1160/TH09-11-0763
PMCID: PMC2949522  PMID: 20694283
gamma-glutamyl carboxylase; warfarin; pharmacogenetics; algorithm
5.  Laboratory and Clinical Outcomes of Pharmacogenetic vs. Clinical Protocols for Warfarin Initiation in Orthopedic Patients 
Background
Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common.
Methods
In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy.
Results
The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, perioperative blood loss, liver disease, INR values, and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (N = 86), and 70% when used prospectively (N = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (N = 178), and 48% in a prospective validation cohort (N = 146). In one month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7%–11.7%) in the pharmacogenetic cohort. The risk of laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.29–0.97).
Conclusions
Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, www.WarfarinDosing.org.
doi:10.1111/j.1538-7836.2008.03095.x
PMCID: PMC2920450  PMID: 18662264
Warfarin; Pharmacogenetics; Dosing Algorithm; Anticoagulants; Orthopedic Surgery

Results 1-5 (5)