We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the International Verapamil SR-Trandolapril Study, where participants were randomized to a β blocker strategy or a calcium channel blocker strategy. Genome-spanning SNP × treatment interaction analyses of non-synonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top three signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (International Verapamil SR-Trandolapril Study whites and Hispanics combined interaction P=0.0038, and 0.0036, respectively). A genetic risk score including rs16982743, rs893184 and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the International Verapamil SR-Trandolapril Study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10−5). In patients with a genetic risk score of zero or 1, calcium channel blocker treatment was associated with lower risk (OR (95% CI) = 0.60 (0.42-0.86)), and in those with a genetic risk score of 2-3, calcium channel blocker treatment was associated with higher risk, OR (95% CI) = 1.31 (1.08-1.59)). These results suggest cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
Pharmacogenomics; Hypertension; antihypertensive agents; cardiovascular outcomes; genetic variation; beta-blockers, calcium channel blockers
The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.
We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.
At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.
Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)
The VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. 1000 samples were analyzed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1±29.4 mg/week) than those with the Asp36Asp genotype (35.8±16.6 mg/week; P<0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.
Warfarin; Pharmacogenetics; VKORC1 Asp36Tyr; polymorphism; Egyptians
Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed.
clinical implementation; pharmacogenetics; pharmacogenomics
To evaluate pregnancy outcomes according to 2009 Institute of Medicine (IOM) gestational weight gain guidelines.
This study is a secondary analysis of a preeclampsia prevention trial among nulliparas carrying singletons. Odds ratios and 95% confidence intervals (adjusted for maternal age, race, smoking, and treatment group) were calculated based on total weight gain below or above the IOM guidelines, stratified by prepregnancy body mass index (BMI). The referent group was weight gain within the guidelines.
Of 8,293 pregnancies, 9.5% had weight gain below, 17.5% within, and 73% above IOM guidelines. With excess weight gain, all BMI categories had an increased risk of hypertensive disorders; normal weight and overweight women also had increased risk of cesarean delivery and infant birth weight at or above the 90th centile but a decreased risk of weight below the10th centile. There were no consistent associations with insufficient weight gain and adverse outcomes.
Excess weight gain was prevalent and associated with an increased risk of hypertensive disorders, cesarean delivery and large for gestational age infants..
The University of Florida and Shands Hospital recently launched a genomic medicine program focused on the clinical implementation of pharmacogenetics called the Personalized Medicine Program. We focus on a preemptive, chip-based genotyping approach that is cost effective, while providing experience that will be useful as genomic medicine moves towards genome sequence data for patients becoming available. The Personalized Medicine Program includes a regulatory body that is responsible for ensuring that evidence-based examples are moved to clinical implementation, and relies on clinical decision support tools to provide healthcare providers with guidance on use of the genetic information. The pilot implementation was with CYP2C19-clopidogrel and future plans include expansion to additional pharmacogenetic examples, along with aiding in implementation in other health systems across Florida.
Purpose of review
To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice.
Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice.
Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics.
clinical implementation; clopidogrel; personalized medicine; pharmacogenetics; warfarin
Aims and objectives
Test the feasibility and validity of a handoff evaluation tool for nurses.
No validated tools exist to assess the quality of handoff communication during change of shift.
Prospective cohort study.
A standardised tool, the Handoff CEX, was developed based on the mini-CEX. The tool consisted of seven domains scored on a 1–9 scale. Nurse educators observed shift-to-shift handoff reports among nurses and evaluated both the provider and recipient of the report. Nurses participating in the report simultaneously evaluated each other as part of their handoff.
Ninety-eight evaluations were obtained from 25 reports. Scores ranged from 3–9 in all domains except communication and setting (4–9). Experienced (>five years) nurses received significantly higher mean scores than inexperienced (≤five years) nurses in all domains except setting and professionalism. Mean overall score for experienced nurses was 7·9 vs 6·9 for inexperienced nurses. External observers gave significantly lower scores than peer evaluators in all domains except setting. Mean overall score by external observers was 7·1 vs. 8·1 by peer evaluators. Participants were very satisfied with the evaluation (mean score 8·1).
A brief, structured handoff evaluation tool was designed that was well-received by participants, was felt to be easy to use without training, provided data about a wide range of communication competencies and discriminated well between experienced and inexperienced clinicians.
Relevance to clinical practice
This tool may be useful for educators, supervisors and practicing nurses to provide training, ongoing assessment and feedback to improve the quality of handoff.
communication; evaluation; handover; nurses; nursing; nursing education; transfer of care
To examine the association of anxiety and depression with pulmonary-specific symptoms of Chronic Obstructive Pulmonary Disease (COPD), and to determine the extent to which disease severity and functional capacity modify this association.
Patients (N = 162) enrolled in the INSPIRE-II study, an ongoing randomized, clinical trial of COPD patients and their caregivers who received either telephone-based coping skills training or education and symptom monitoring. Patients completed a psychosocial test battery including: Brief Fatigue Inventory, St. George’s Respiratory Questionnaire, UCSD Shortness of Breath Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory. Measures of disease severity and functional capacity (i.e., FEV1 and six-minute walk test) were also obtained.
After covariate adjustment, higher anxiety and depression levels were associated with greater fatigue levels (ps < .001, ΔR2 = 0.16 and 0.29, respectively), shortness of breath (ps < .001, ΔR2 = 0.12 and 0.10), and frequency of COPD symptoms (ps < .001, ΔR2 = 0.11 and 0.13). In addition, functional capacity was a moderator of anxiety and pulmonary-specific COPD symptoms. The association between anxiety and shortness of breath (p = 0.009) and frequency of COPD symptoms (p = 0.02) was greater among patients with lower functional capacity.
Anxiety and depression were associated with higher levels of fatigue, shortness of breath, and frequency of COPD symptoms. It is important for clinicians to be aware of the presence of anxiety and depression in COPD patients, which appears to correlate with pulmonary-specific COPD symptoms, especially in patients with lower functional capacity. Prospective design studies are needed to elucidate the causal relationships between anxiety and depression and pulmonary-specific symptoms in COPD patients.
anxiety; depression; COPD
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
clinicaltrials.gov; Identifiers: NCT00799396 and NCT00370045
pharmacogenomics; platelets; percutaneous coronary intervention; PEAR1; CYP2C19
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.
epithelial sodium channel; hypertension; International Verapamil SR Trandolapril Study; neural precursor cell expressed developmentally down-regulated 4 like; Pharmacogenomic Evaluation of Antihypertensive Responses; pharmacogenetics
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.
beta-blocker; diuretics; hypertension; pharmacogenetics; polymorphisms blood pressure
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.
hydrochlorothiazide; hypertension; pharmacogenomics; blood pressure; YEATS4; diuretics
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.
clarithromycin; roxithromycin; protein precipitation; LC-MS; human plasma
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.
Hypertension; DASH diet; Blood pressure; Adherence; Psychological testing; Non-pharmacological treatment
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.
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.
Cardiometabolic syndrome; African-Americans; Compliance; Inflammation; Hypertension
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.
hypertension; GRK4; atenolol; beta-blocker; outcomes; ADRB1; pharmacogenetics
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.
dichloroacetate; glutathione transferase zeta; maleylacetoacetate isomerase; pharmacogenetics; toxicogenetics; tyrosine metabolism
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.
Depression; Exercise; Sertraline; Heart rate variability; Inflammation; Biomarkers; antidepressant medication; SSRI
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.
AHA Scientific Statements; genetics
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.
cytochrome P450; CYP; CYP3A5 genotype; pharmacogenetics; atorvastatin; clarithromycin; drug interaction
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.
Antihypertensive drugs; beta-blockers; calcium channel blockers; genetics; pharmacogenetics; pharmacogenomics; thiazide diuretics