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1.  Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes 
Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.
Methods and Results
We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10−9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).
Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.
Clinical Trial Registration Information; Identifiers: NCT00799396 and NCT00370045
PMCID: PMC3715320  PMID: 23392654
pharmacogenomics; platelets; percutaneous coronary intervention; PEAR1; CYP2C19
2.  Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics 
Journal of hypertension  2013;31(4):698-704.
Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers.
Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment.
Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18–96.25)].
NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide.
PMCID: PMC3756535  PMID: 23353631
epithelial sodium channel; hypertension; International Verapamil SR Trandolapril Study; neural precursor cell expressed developmentally down-regulated 4 like; Pharmacogenomic Evaluation of Antihypertensive Responses; pharmacogenetics
4.  Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives – Results from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study 
To date, 39 SNPs have been associated with blood pressure (BP) or hypertension (HTN) in genome-wide association studies (GWAS) in Caucasians. Our hypothesis is that the loci/SNPs associated with BP/HTN are also associated with BP response to antihypertensive drugs.
Methods and Results
We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses (PEAR) study. Linear regression analysis was performed in Caucasians for each SNP in an additive model adjusting for baseline BP, age, gender and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations and empirical p values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M GWAS chips. In Caucasians, no SNPs reached Bonferroni-corrected alpha of 0.0014, six reached nominal significance (p<0.05) and 3 were associated with atenolol BP response at p < 0.01. The genetic score of the atenolol BP lowering alleles was associated with response to atenolol (p =3.3*10−6 for SBP; p=1.6*10−6 for DBP). The genetic score of the HCTZ BP lowering alleles was associated with response to HCTZ (p = 0.0006 for SBP; p = 0.0003 for DBP). Both risk score p values were < 0.01 based on the empirical distribution from the permutation test.
These findings suggest selected signals from hypertension GWAS may predict BP response to atenolol and HCTZ when assessed through risk scoring.
PMCID: PMC3529147  PMID: 23087401
beta-blocker; diuretics; hypertension; pharmacogenetics; polymorphisms blood pressure
5.  Association of Chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression 
The pharmacogenomics journal  2012;13(3):257-263.
A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and hydrochlorothiazide response in an independent sample of 746 Caucasians and African-Americans randomized to hydrochlorothiazide or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4mmHg, P=0.0275; diastolic: 2.5mmHg, P=0.0196) responses to hydrochlorothiazide vs. T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as hydrochlorothiazide-specific. Expression analyses in hydrochlorothiazide-treated African-Americans showed differential leukocyte YEATS4 expression between rs7297610 genotype groups at baseline (P=0.024), and reduced 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.
PMCID: PMC3360116  PMID: 22350108
hydrochlorothiazide; hypertension; pharmacogenomics; blood pressure; YEATS4; diuretics
6.  Simplified method for determination of clarithromycin in human plasma using protein precipitation in a 96-well format and liquid chromatography-tandem mass spectrometry 
A simplified method to determine clarithromycin concentrations in human plasma using protein precipitation in a 96-well plate and liquid chromatography tandem mass spectrometry was developed and validated. Plasma proteins were precipitated with acetonitrile and roxithromycin was used as the internal standard. After vortex-mixing and centrifugation, the supernatants were directly injected onto a Phenomenex Luna Phenyl-Hexyl column (50 × 2.0 mm I.D., 3μm). The mobile phase consisted of water and methanol (30:70; v/v) containing 0.1% formic acid and 5 mM ammonium acetate. The flow rate was 0.22 mL/min and the total run time (injection to injection) was less than 3 minutes. Detection of the analytes was achieved using positive ion electrospray tandem mass spectrometry in selected reaction monitoring (SRM) mode. The linear standard curve ranged from 100 to 5,000 ng/mL and the precision and accuracy (inter- and intrarun) were within 8.3% and 6.3%, respectively. The method was successfully used to determine clarithromycin concentrations in human plasma samples obtained from healthy subjects who were given clarithromycin 500 mg for three days. The method is rapid, simple, precise and directly applicable to clarithromycin pharmacokinetic studies.
PMCID: PMC3832059  PMID: 18639501
clarithromycin; roxithromycin; protein precipitation; LC-MS; human plasma
7.  Determinants and Consequences of Adherence to the DASH Diet in African American and White Adults with High Blood Pressure: Results from the ENCORE Trial 
Although the DASH (Dietary Approaches to Stop Hypertension) diet is an accepted non-pharmacologic treatment for hypertension, little is known about what patient characteristics affect dietary adherence and what level of adherence is needed to reduce blood pressure (BP).
To determine what factors predict dietary adherence and the extent to which dietary adherence is necessary to produce clinically meaningful BP reductions.
Ancillary study of the ENCORE trial-- a 16-week randomized clinical trial of diet and exercise.
Participants included 144 sedentary, overweight or obese adults (BMI’s 25-39.9 kg/m2) with high BP (systolic BP 130-159 and/or diastolic BP 85-99 mm Hg).
Patients were randomized to one of 3 groups: DASH diet alone (DASH-A), DASH diet plus weight management (DASH+WM), and Usual diet controls (UC).
Main outcome measures
Our primary outcomes were a composite index of adherence to the DASH diet and clinic BP.
Statistical analyses performed
General linear models were used to compare treatment groups on post-treatment adherence to the DASH diet. Linear regression was used to examine potential predictors of post-treatment DASH adherence. Analysis of covariance (ANCOVA) was used to examine the relation of adherence to the DASH diet and BP.
Participants in the DASH+WM (16.1 SBP [95% CI = 13.0, 19.2], 9.9 DBP [95% CI = 8.1, 11.6] mm Hg) and DASH+A (11.2 SBP [95% CI = 8.1, 14.3], 7.5 DBP [95% CI = 5.8, 9.3] mm Hg) groups showed significant reductions in BP in comparison with UC participants (3.4 SBP [95% CI = 0.4, 6.4], DBP 3.8 [95% CI = 2.2, 5.5] mm Hg). Greater post-treatment consumption of DASH foods was noted in both the DASH-A (M=6.20 [95% CI = 5.83, 6.57]) and DASH+WM groups (M=6.23 [95% CI = 5.88, 6.59]) compared to UC (M=3.66 [95% CI = 3.30, 4.01]) (p<.0001), and greater adherence to the DASH diet was associated with larger reductions in clinic SBP and DBP (p ≤.01). Only ethnicity predicted dietary adherence, with African Americans less adherent to the DASH diet compared to whites (4.68 [95% CI = 4.34, 5.03] v 5.83 [95% CI = 5.50, 6.11], p< .001).
Greater adherence to the DASH diet was associated with larger BP reductions independent of weight loss. African Americans were less likely to be adherent to the DASH dietary eating plan compared to whites, suggesting that culturally sensitive dietary strategies may be needed to improve adherence to the DASH diet.
PMCID: PMC3483427  PMID: 23000025
Hypertension; DASH diet; Blood pressure; Adherence; Psychological testing; Non-pharmacological treatment
8.  Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study 
PLoS ONE  2013;8(10):e76984.
We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.
PMCID: PMC3792156  PMID: 24116192
9.  Changes in Central Aortic Pressure, Endothelial Function and Biomarkers in Hypertensive African-Americans with the Cardiometabolic Syndrome: Comparison of Amlodipine/Olmesartan versus Hydrochlorothiazide/Losartan 
Cardiorenal Medicine  2013;3(4):221-231.
Sixty-six self-identified African-American subjects with stage 1 and 2 hypertension and characteristics of the cardiometabolic syndrome were treated with amlodipine/olmesartan (A/O) versus losartan/hydrochlorothiazide (L/H) for 20 weeks in an open-label, active comparator fashion. Subjects not meeting a blood pressure (BP) value of <125/75 mm Hg on either regimen at week 14 were placed on additional or alternative therapy. After 20 weeks of therapy, systolic BP was reduced by 34.6 ± 4.2 mm Hg in the A/O group and by 27.0 ± 4.1 mm Hg in the L/H group (p = 0.012 A/O vs. L/H). Diastolic BP was reduced by 16.9 ± 2.0 mm Hg in the A/O group and by 12.3 ± 2.0 mm Hg in the L/H group (p = 0.022 A/O vs. L/H). There was a substantial increase in endothelial function of 44 and 103% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H). Central aorta augmentation pressure was significantly reduced by 42% with the A/O treatment, and a smaller, significant reduction of 28% was observed with the L/H treatment (p = 0.034 A/O vs. L/H). There was a reduction in sIL-6 levels of 20 and 33%, a reduction in serum leptin levels of 22 and 40%, and an increase in serum adiponectin of 19 and 46% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H for each biomarker). Treatment with A/O after 14 weeks reduced pulse wave velocity by 22% (p = 0.011 time comparison), whereas L/H treatment had no significant effect. Our findings suggest that, in addition to effective BP reduction, A/O differentially regulates markers of inflammation and obesity, thereby potentially providing greater vascular protection.
PMCID: PMC3901604  PMID: 24474950
Cardiometabolic syndrome; African-Americans; Compliance; Inflammation; Hypertension

Hypertension  2012;60(4):957-964.
G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized three nonsynonymous GRK4 SNPs, R65L (rs2960306), A142V (rs1024323) and A486V (rs1801058) would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long term cardiovascular outcomes (all cause, death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 SNPs were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In Caucasians and African Americans, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1 ± 6.8 vs −6.8 ± 7.1 vs −5.3 ± 6.4 mmHg in participants with 0, 1 and 2 copies of 65L-142V respectively; p=0.0088). 1460 participants with hypertension and coronary artery disease from the INternational VErapamil SR / Trandolapril STudy (INVEST) were genotyped and variant alleles of all three GRK4 SNPs were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (Odds ratio 2.29 [1.48–3.55], p=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R-homozygotes, suggesting a potential interaction between these two genes.
PMCID: PMC3462355  PMID: 22949529
hypertension; GRK4; atenolol; beta-blocker; outcomes; ADRB1; pharmacogenetics
11.  Human Polymorphisms in the Glutathione Transferase Zeta 1/Maleylacetoacetate Isomerase Gene Influence the Toxicokinetics of Dichloroacetate 
Journal of clinical pharmacology  2011;52(6):10.1177/0091270011405664.
Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1) maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-13C-DCA when it was administered at either environmentally (μg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA’s adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.
PMCID: PMC3786668  PMID: 21642471
dichloroacetate; glutathione transferase zeta; maleylacetoacetate isomerase; pharmacogenetics; toxicogenetics; tyrosine metabolism
12.  Exercise and Pharmacological Treatment of Depressive Symptoms in Patients with Coronary Heart Disease: Results from the UPBEAT Study 
To assess the efficacy of exercise and antidepressant medication in reducing depressive symptoms and improving cardiovascular biomarkers in depressed patients with coronary heart disease (CHD).
Although there is good evidence that clinical depression is associated with poor prognosis, optimal therapeutic strategies are currently not well-defined.
101 outpatients with CHD and elevated depressive symptoms underwent assessment of depression including a psychiatric interview and the Hamilton Rating Scale for Depression (HAM-D). Participants were randomized to 4 months of aerobic exercise (3 times/week), sertraline (50-200 mg/day), or placebo. Additional assessments of cardiovascular biomarkers included measures of heart rate variability (HRV), endothelial function, baroreflex sensitivity, inflammation, and platelet function.
After 16 weeks, all groups showed improvement on HAM-D scores. Participants in both aerobic exercise (M= −7.5 [95% CI = −9.8, −5.0]) and sertraline (M= −6.1 [95% CI = −8.4, −3.9] achieved larger reductions in depressive symptoms compared to placebo (M= −4.5 [95% CI = −7.6, −1.5]; p = .034); exercise and sertraline were equally effective in reducing depressive symptoms (p = .607). Exercise and medication tended to result in greater improvements in HRV compared to placebo (p = .052); exercise tended to result in greater improvements in HRV compared to sertraline (p =.093)
Both exercise and sertraline resulted in greater reductions in depressive symptoms compared to placebo in CHD patients. Evidence that active treatments may also improve cardiovascular biomarkers suggests that they may have a beneficial effect on clinical outcomes as well as quality of life.
PMCID: PMC3498445  PMID: 22858387
Depression; Exercise; Sertraline; Heart rate variability; Inflammation; Biomarkers; antidepressant medication; SSRI
13.  The Role of Clinical Experience in Speech-Language Pathologists' Perception of Subphonemic Detail in Children's Speech 
This study examined whether experienced speech-language pathologists differ from inexperienced people in their perception of phonetic detail in children's speech.
Convenience samples comprising 21 experienced speech-language pathologist and 21 inexperienced listeners participated in a series of tasks in which they made visual-analog scale (VAS) ratings of children's natural productions of target /s/-/θ/, /t/-/k/, and /d/-/ɡ/ in word-initial position. Listeners rated the perception distance between individual productions and ideal productions.
The experienced listeners' ratings differed from inexperienced listeners' in four ways: they had higher intra-rater reliability, they showed less bias toward a more frequent sound, their ratings were more closely related to the acoustic characteristics of the children's speech, and their responses were related to a different set of predictor variables.
Results suggest that experience working as a speech-language pathologist leads to better perception of phonetic detail in children's speech. Limitations and future research are discussed.
PMCID: PMC3733991  PMID: 22230182
15.  Effect of Cytochrome P450 3A5 Genotype on Atorvastatin Pharmacokinetics and Its Interaction with Clarithromycin 
Pharmacotherapy  2011;31(10):942-950.
Study Objective
To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin.
Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study.
Clinical research center at a teaching hospital.
Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors).
In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days.
Measurements and Main Results
Pharmacokinetic parameters of both forms of atorvastatin—atorvastatin acid and atorvastatin lactone—were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin’s muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8–64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6–42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC0−∞ of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049).
Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.
PMCID: PMC3712822  PMID: 21950641
cytochrome P450; CYP; CYP3A5 genotype; pharmacogenetics; atorvastatin; clarithromycin; drug interaction
16.  Advancing management of hypertension through pharmacogenomics 
Annals of medicine  2012;44(0 1):S17-S22.
Hypertension is the most common, chronic disease in the world, and there are many effective pharmacological agents available for its treatment. Despite the plethora of treatment options, data across the globe suggest that blood pressure control rates are <50%, a fact likely influenced in part by the inability to predict the antihypertensive drug likely to be most effective for an individual patient. Pharmacogenomics in hypertension holds the promise of identifying genetic biomarkers for antihypertensive drug response, which might be used in the future in treatment selection. Research in the field is also likely to enhance our understanding of hypertension and the mechanisms by which the various drugs produce efficacy. There are several examples in the literature of genes with relatively strong data on associations of genetic polymorphisms with antihypertensive response; the data on ADRB1, CACNB2, and NEDD4L are detailed as examples. Substantial additional data in hypertension pharmacogenomics are expected to be forthcoming from recently completed genome-wide association studies. Increased collaboration among research groups will help insure successful discoveries from these large-scale studies. The next decade should clearly define the potential clinical implications of the research in hypertension pharmacogenomics that is currently in progress.
PMCID: PMC3686275  PMID: 22713143
Antihypertensive drugs; beta-blockers; calcium channel blockers; genetics; pharmacogenetics; pharmacogenomics; thiazide diuretics
17.  Understanding prognostic benefits of exercise and antidepressant therapy for persons with depression and heart disease: the UPBEAT study – rationale, design, and methodological issues 
Depression is relatively common in patients with coronary heart disease (CHD) and is associated with worse prognosis. Recently there has been interest in evaluating the impact of treating depression on clinical outcomes. Anti-depressant medications have been shown to be safe and efficacious for many patients; exercise also may be effective for treating depression and may also improve cardiopulmonary functioning. However, methodological limitations of previous studies have raised questions about the value of exercise, and no study has compared the effects of exercise with standard anti-depressant medication in depressed cardiac patients.
UPBEAT is a randomized clinical trial (RCT) funded by NHLBI to evaluate the effects of sertraline or exercise compared to placebo on depression and biomarkers of cardiovascular risk in patients with CHD and elevated depressive symptoms.
The UPBEAT study includes 200 stable CHD patients with scores on the Beck Depression Inventory (BDI) ≥ 9 randomized to 4 months of treatment with aerobic exercise, sertraline, or placebo. The primary outcomes include depressive symptoms determined by clinical ratings on the Hamilton Rating Scale for Depression (HAM-D) and measures of heart rate variability (HRV), baroreflex control (BRC), vascular function (i.e., flow-mediated dilation (FMD)), and measures of inflammation and platelet aggregation.
This article reviews the rationale and design of UPBEAT and addresses several key methodologic issues that were carefully considered in the development of this protocol: the use of a placebo control condition in depressed cardiac patients, study design, and selection of intermediate endpoints or biomarkers of cardiovascular risk.
This study is not powered to assess treatment group differences in CHD morbidity and mortality. Intermediate endpoints are not equivalent to ‘hard’ clinical events and further studies are needed to determine the clinical significance of these biomarkers.
The UPBEAT study is designed to assess the efficacy of exercise in treating depression in cardiac patients and evaluates the impact of treating depression on important biomarkers of cardiovascular risk.
PMCID: PMC3677197  PMID: 17942470
18.  Urate Transporter Gene SLC22A12 Polymorphisms Associated with Obesity and Metabolic Syndrome in Caucasians with Hypertension 
Kidney & blood pressure research  2012;35(6):477-482.
Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects.
Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825.
In Caucasians, SLC22A12 SNPs were associated with the body mass index (BMI). rs11602903 was associated with BMI (p < 0.0001), waist circumference (p = 0.003), HDL cholesterol (p = 0.018) and the metabolic syndrome (p = 0.033), and accounted for 7% of the variation of BMI in Caucasians. In African Americans, SLC22A12 SNP rs11602903 was not associated with BMI, waist circumference, HDL cholesterol or triglycerides.
The URAT1 gene SLC22A12 polymorphism may play a role in obesity and the metabolic syndrome in Caucasian hypertensive subjects.
PMCID: PMC3480975  PMID: 22688828
Hypertension; Metabolic syndrome; Obesity; SLC22A12 polymorphisms; URAT1; Uric acid
19.  Prevention of Maternal and Congenital Cytomegalovirus Infection 
Congenital cytomegalovirus (CMV) infection is an important cause of hearing impairment, mental retardation and cerebral palsy. Principal sources of infection during pregnancy are young children and intimate contacts. Prevention of maternal and congenital CMV infection depends on counseling women regarding the sources of infection and hygienic measures that might prevent infection. There is currently insufficient evidence to support use of antiviral treatment or passive immunization for post-exposure prophylaxis of pregnant women or as a maternal treatment aimed at preventing fetal infection. Vaccines for CMV are under development but it will be a number of years before one is licensed.
PMCID: PMC3347968  PMID: 22510635
Cytomegalovirus; congenital infection; CMV prevention; prenatal counseling
20.  Computer-Facilitated Substance Use Screening and Brief Advice for Teens in Primary Care: An International Trial 
Pediatrics  2012;129(6):1072-1082.
Primary care providers need effective strategies for substance use screening and brief counseling of adolescents. We examined the effects of a new computer-facilitated screening and provider brief advice (cSBA) system.
We used a quasi-experimental, asynchronous study design in which each site served as its own control. From 2005 to 2008, 12- to 18-year-olds arriving for routine care at 9 medical offices in New England (n = 2096, 58% females) and 10 in Prague, Czech Republic (n = 589, 47% females) were recruited. Patients completed measurements only during the initial treatment-as-usual study phase. We then conducted 1-hour provider training, and initiated the cSBA phase. Before seeing the provider, all cSBA participants completed a computerized screen, and then viewed screening results, scientific information, and true-life stories illustrating substance use harms. Providers received screening results and “talking points” designed to prompt 2 to 3 minutes of brief advice. We examined alcohol and cannabis use, initiation, and cessation rates over the past 90 days at 3-month follow-up, and over the past 12 months at 12-month follow-up.
Compared with treatment as usual, cSBA patients reported less alcohol use at follow-up in New England (3-month rates 15.5% vs 22.9%, adjusted relative risk ratio [aRRR] = 0.54, 95% confidence interval 0.38–0.77; 12-month rates 29.3% vs 37.5%, aRRR = 0.73, 0.57–0.92), and less cannabis use in Prague (3-month rates 5.5% vs 9.8%, aRRR = 0.37, 0.17–0.77; 12-month rates 17.0% vs 28.7%, aRRR = 0.47, 0.32–0.71).
Computer-facilitated screening and provider brief advice appears promising for reducing substance use among adolescent primary care patients.
PMCID: PMC3362902  PMID: 22566420
adolescents; substance use; primary care; screening; brief intervention; computer-assisted; alcohol; cannabis
22.  Pathway analysis of genome-wide data improves warfarin dose prediction 
BMC Genomics  2013;14(Suppl 3):S11.
Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations.
Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association.
Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.
PMCID: PMC3829086  PMID: 23819817
23.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
24.  Nurses’ workarounds in acute healthcare settings: a scoping review 
Workarounds circumvent or temporarily ‘fix’ perceived workflow hindrances to meet a goal or to achieve it more readily. Behaviours fitting the definition of workarounds often include violations, deviations, problem solving, improvisations, procedural failures and shortcuts. Clinicians implement workarounds in response to the complexity of delivering patient care. One imperative to understand workarounds lies in their influence on patient safety. This paper assesses the peer reviewed empirical evidence available on the use, proliferation, conceptualisation, rationalisation and perceived impact of nurses’ use of workarounds in acute care settings.
A literature assessment was undertaken in 2011–2012. Snowballing technique, reference tracking, and a systematic search of twelve academic databases were conducted to identify peer reviewed published studies in acute care settings examining nurses’ workarounds. Selection criteria were applied across three phases. 58 studies were included in the final analysis and synthesis. Using an analytic frame, these studies were interrogated for: workarounds implemented in acute care settings by nurses; factors contributing to the development and proliferation of workarounds; the perceived impact of workarounds; and empirical evidence of nurses’ conceptualisation and rationalisation of workarounds.
The majority of studies examining nurses’ workarounds have been published since 2008, predominantly in the United States. Studies conducted across a variety of acute care settings use diverse data collection methods. Nurses’ workarounds, primarily perceived negatively, are both individually and collectively enacted. Organisational, work process, patient-related, individual, social and professional factors contribute to the proliferation of workarounds. Group norms, local and organisational culture, ‘being competent’, and collegiality influence the implementation of workarounds.
Workarounds enable, yet potentially compromise, the execution of patient care. In some contexts such improvisations may be deemed necessary to the successful implementation of quality care, in others they are counterproductive. Workarounds have individual and cooperative characteristics. Few studies examine nurses’ individual and collective conceptualisation and rationalisation of workarounds or measure their impact. The importance of displaying competency (image management), collegiality and organisational and cultural norms play a role in nurses’ use of workarounds.
PMCID: PMC3663687  PMID: 23663305
Workaround; Violation; Deviation; Short cut; First order problem solving; Patient safety; Procedural failure
25.  Effects of high fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects 
Metabolism  2011;61(5):641-651.
It is unclear whether high fructose corn syrup (HFCS), which contains a higher amount of fructose and provides an immediate source of free fructose, induces greater systemic concentrations of fructose as compared to sucrose. It is also unclear whether exposure to higher levels of fructose leads to increased fructose-induced adverse effects. The objective was to prospectively compare the effects of HFCS- versus sucrose-sweetened soft drinks on acute metabolic and hemodynamic effects.
Forty men and women consumed 24 oz of HFCS- or sucrose-sweetened beverages in a randomized crossover design study. Blood and urine samples were collected over 6 hr. Blood pressure, heart rate, fructose, and a variety of other metabolic biomarkers were measured.
Fructose area under the curve and maximum concentration, dose normalized glucose area under the curve and maximum concentration, relative bioavailability of glucose, changes in postprandial concentrations of serum uric acid, and systolic blood pressure maximum levels were higher when HFCS-sweetened beverages were consumed as compared to sucrose-sweetened beverages.
Compared to sucrose, HFCS leads to greater fructose systemic exposure and significantly different acute metabolic effects.
PMCID: PMC3306467  PMID: 22152650
soft drinks; sweetened beverages; adverse metabolic effects; carbohydrate metabolism

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