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.
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
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.
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.
Hypertension; Metabolic syndrome; Obesity; SLC22A12 polymorphisms; URAT1; Uric acid
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.
Cytomegalovirus; congenital infection; CMV prevention; prenatal counseling
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.
adolescents; substance use; primary care; screening; brief intervention; computer-assisted; alcohol; cannabis
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.
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
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.
Workaround; Violation; Deviation; Short cut; First order problem solving; Patient safety; Procedural failure
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.
soft drinks; sweetened beverages; adverse metabolic effects; carbohydrate metabolism
editorials; pharmacogenetics; polymorphism genetics
Although the DASH (Dietary Approaches to Stop Hypertension) diet has been shown to lower blood pressure (BP) in short-term feeding studies, it has not been shown to lower BP among free-living individuals, nor has it been shown to alter cardiovascular biomarkers of risk.
To compare the DASH diet alone or combined with a weight management program with usual diet controls among participants with prehypertension or stage 1 hypertension (systolic BP, 130–159 mm Hg; or diastolic BP, 85–99 mm Hg).
Design and Setting
Randomized, controlled trial in a tertiary care medical center with assessments at baseline and 4 months. Enrollment began October 29, 2003, and ended July 28, 2008.
Overweight or obese, unmedicated outpatients with high BP (N = 144).
Usual diet controls, DASH diet alone, and DASH diet plus weight management.
The main outcome measure is BP measured in the clinic and by ambulatory BP monitoring. Secondary outcomes included pulse wave velocity, flow-mediated dilation of the brachial artery, baroreflex sensitivity, and left ventricular mass.
Clinic-measured BP was reduced by 16.1/9.9 mm Hg (DASH plus weight management); 11.2/7.5 mm (DASH alone); and 3.4/3.8 mm (usual diet controls) (P < .001). A similar pattern was observed for ambulatory BP (P < .05). Greater improvement was noted for DASH plus weight management compared with DASH alone for pulse wave velocity, baroreflex sensitivity, and left ventricular mass (all P < .05).
For overweight or obese persons with above-normal BP, the addition of exercise and weight loss to the DASH diet resulted in even larger BP reductions, greater improvements in vascular and autonomic function, and reduced left ventricular mass. Key words: Hypertension, Exercise, DASH diet, Blood pressure, Left ventricular mass
Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
Thiazides and β-blockers cause adverse metabolic effects (AMEs), but whether these effects share predictors with blood pressure (BP) response is unknown. We aimed to determine whether AMEs are correlated with BP response in uncomplicated hypertensives.
In a multicenter, open-label, parallel-group trial, we enrolled 569 persons, aged 17–65, with random assignment to 9 weeks of daily hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by 9 weeks of add-on therapy with the alternate agent. Measurements included home BP, averaged over 1 week, weight and fasting levels of serum glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and uric acid (UA) before and after monotherapy and after add-on therapy.
Increases in UA correlated with reductions in systolic BP (SBP) (r = −0.18; P = 0.003) and diastolic BP (DBP) (r = −0.20; P = 0.001) following HCTZ monotherapy and add-on therapy (r = −0.27 and r = −0.21, respectively; both P < 0.001). After adjustment for age, race, gender, and baseline body mass index (BMI), only the correlation between UA and DBP response became nonsignificant. Reductions in HDL correlated with systolic response following atenolol monotherapy (r = 0.18; P = 0.002) and with systolic and diastolic response following add-on therapy (r = 0.30 and r = 0.24, respectively; both P < 0.0001). These correlations remained significant after covariate adjustment. BP responses were not correlated with changes in glucose, LDL, triglycerides, or weight following either therapy.
BP response correlated with changes in UA following HCTZ therapy and HDL following atenolol therapy. No other significant correlations were observed between BP response and AMEs, suggesting that these effects generally do not share predictors. Patients should be monitored for AMEs, regardless of BP response.
thiazide diuretics; atenolol; β-blockers; blood pressure; hydrochlorothiazide; hypertension; metabolic effects
In the past few decades, consumption of added sugars has increased dramatically. Studies have linked high sugar intake with increased risk for a number of diseases. Importantly, fructose, a component of sugar, has been linked with the development of features of metabolic syndrome. This study determined if single nucleotide polymorphisms in genes involved in fructose transport (solute carrier family 2 facilitated glucose transporter, member 2 (SLC2A2) and solute carrier family 2 facilitated glucose/fructose transporter, member 5 (SLC2A5)) and metabolism (ketohexokinase (KHK)) affect inter-individual variability in metabolic phenotypes, such as increased serum uric acid levels.
The influence of SLC2A2, SLC2A5, and KHK SNPs on metabolic phenotypes was tested in 237 European Americans and 167 African Americans from the Pharmacogenomic Evaluation and Antihypertensive Responses (PEAR) study. Using baseline untreated fasting data, associations were considered significant if p≤0.005. These SNPs were then evaluated for potential replication (p≤0.05) using data from the Genetic Epidemiology of Responses to Antihypertensives (GERA) studies.
SLC2A5 rs5438 was associated with an increase in serum uric acid in European American males. However, we were unable to replicate the association in GERA. The minor allele of SLC2A2 rs8192675 showed an association with lower high-density lipoproteins in European Americans (A/A: 51.0 mg/dL, A/G: 47.0 mg/dL, G/G: 41.5 mg/dL, p = 0.0034) in PEAR. The association between rs8192675 and lower high-density lipoproteins was replicated in the combined European American GERA study samples (A/A: 47.6 mg/dL, A/G: 48.6 mg/dL, G/G: 41.9 mg/dL, p = 0.0315).
The association between SLC2A2 rs8192675 and high-density lipoproteins suggests the polymorphism may play a role in influencing high-density lipoproteins and thus metabolic risk of cardiovascular disease.
Recently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).
INVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.
We observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.
Our results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.
HMGA1; Type 2 diabetes; Genetics
The detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a160 kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3 kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5 hours to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus.
pattern recognition; next-generation sequencing analysis; indels; rare variants; FKBP5; HLA
Patients vary in their responses to drug therapy, and some of that variability is genetically-determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented: cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and anti-platelet agents. A brief view of potential pathways to implementation is presented.
genetics; pharmacogenetics; pharmacogenomics; drug therapy
Due to time-dependent confounding by blood pressure and differential loss to follow-up, it is difficult to estimate the effectiveness of aggressive versus conventional antihypertensive combination therapies in non-randomized comparisons.
We utilized data from 22,576 hypertensive coronary artery disease patients, prospectively enrolled in the INternational VErapamil-Trandolapril STudy (INVEST). Our post-hoc analyses did not consider the randomized treatment strategies, but instead defined exposure time-dependently as aggressive treatment (≥3 concomitantly used antihypertensive medications) versus conventional treatment (≤2 concomitantly used antihypertensive medications). Study outcome was defined as time to first serious cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or all-cause death). We compared hazard ratio (HR) estimates for aggressive vs. conventional treatment from a Marginal Structural Cox Model (MSCM) to estimates from a standard Cox model. Both models included exposure to antihypertensive treatment at each follow-up visit, demographics, and baseline cardiovascular risk factors, including blood pressure. The MSCM further adjusted for systolic blood pressure at each follow-up visit, through inverse probability of treatment weights.
2,269 (10.1%) patients experienced a cardiovascular event over a total follow-up of 60,939 person-years. The HR for aggressive treatment estimated by the standard Cox model was 0.96 (95% confidence interval 0.87-1.07). The equivalent MSCM, which was able to account for changes in systolic blood pressure during follow-up, estimated a HR of 0.81 (95% CI 0.71-0.92).
Using a MSCM, aggressive treatment was associated with a lower risk for serious cardiovascular outcomes compared to conventional treatment. In contrast, a standard Cox model estimated similar risks for aggressive and conventional treatments.
Clinicaltrials.gov Identifier: NCT00133692
Blood pressure; Hypertension; Time-dependent confounding; Marginal structural models