β‐Blockers’ heart rate (HR)‐lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β‐blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β‐blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single‐nucleotide polymorphisms (SNPs) previously associated with the HR response to β‐blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β‐blocker used in the PEAR (n = 757), PEAR‐2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR‐2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β‐blockers in whites (rs1042714 C‐allele carriers, meta‐analysis β = –0.95 beats per minute [bpm], meta‐analysis P = 3×10–4; rs1042713 A‐allele carriers, meta‐analysis β = –1.15 bpm, meta‐analysis P = 2×10–3). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β‐blockade in hypertensive patient cohorts.

Background For many indications, the negative chronotropic effect of β‐blockers is important to their efficacy, yet the heart rate ( HR ) response to β‐blockers varies. Herein, we sought to use a genome‐wide association approach to identify novel single nucleotide polymorphisms ( SNP s) associated with HR response to β‐blockers. Methods and Results We first performed 4 genome‐wide association analyses for HR response to atenolol (a β1‐adrenergic receptor blocker) as: (1) monotherapy or (2) add‐on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta‐analysis was then performed between the genome‐wide association analysis performed in PEAR atenolol monotherapy and add‐on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNP s associated with HR response to atenolol at a P <1E‐05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1‐adrenergic receptor blocker). From the genome‐wide association meta‐analyses, SNP rs17117817 near olfactory receptor family10 subfamily‐p‐member1 ( OR 10P1 ), and SNP rs2364349 in sorting nexin‐9 ( SNX 9 ) replicated in blacks. The combined studies meta‐analysis P values for the rs17117817 and rs2364349 reached genome‐wide significance (rs17117817G‐allele; Meta‐β=5.53 beats per minute, Meta‐ P =2E‐09 and rs2364349 A‐allele; Meta‐β=3.5 beats per minute, Meta‐ P =1E‐08). Additionally, SNP s in the OR 10P1 and SNX 9 gene regions were also associated with HR response in whites. Conclusions This study highlights OR 10P1 and SNX 9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Introduction: Congestion remains the most common reason for admission of heart failure (HF) representing a high unmet medical need. Increased vasopressin (AVP) levels are common in these patients c...

SummaryVenous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10%) mg/kg (80% of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10%) mg/kg (target adult dose adjusted for patient’s weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dosenormalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY® population PK model (94% of trough concentrations were within the 80% prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration–ECT and –aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.Institution where work was performed: Main clinical study site: Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.This study is registered at ClinicalTrials.gov (NCT00844415).

Introduction: Dabigatran etexilate (DE) is an oral direct thrombin inhibitor. It is approved for multiple indications in adults. HYPOTHESIS: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in adolescents with venous thromboembolism (VTE). METHODS: Patients aged 12-< 18 years, who had completed anticoagulation treatment with low molecular weight heparin or an oral anticoagulant for VTE as required for clinical management, received DE twice daily for 3 days at exploratory doses targeting 1.71 mg/kg for the first dose, followed by 5 doses of 2.14 mg/kg, if there were no safety concerns. Blood samples for PK/PD purposes were taken at peak (2 h after morning dose) and trough (12 h after the evening dose). Observed plasma concentrations of total dabigatran were compared to simulated concentrations based on a population-pharmacokinetic (PopPK) model. The PK/PD relationships between total dabigatran plasma concentrations and activated partial thromboplastin (aPTT), diluted thrombi...

BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 ( EGFR/HER2 ) gene amplification or EGFR ‐activating mutations. METHODS Patients with previously treated but ErbB inhibitor‐naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH‐positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR ‐activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single‐agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker‐driven approach using a low‐frequency biomarker for patient selection across multiple tumor types can be challenging. Cancer 2013;119:3043—3051 . © 2013 American Cancer Society .

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.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

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 that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, 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 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1±6.8 versus −6.8±7.1 versus −5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P =0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms 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 that 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 2 genes.

Background— Although numerous single-nucleotide polymorphisms (SNPs) in chromosome 9p21 have been associated with coronary artery disease (CAD) and incident myocardial infarction (MI) in whites, there are limited and conflicting reports on the association of this locus with prognosis in whites with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD. Methods and Results— We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertension patients with CAD of multiple races/ethnicities in INVEST-GENES (the International Verapamil SR Trandolapril Study Genetic Substudy) (n=1460 and n=5979 for 2 SNPs) with replication testing of 4 SNPs in the INFORM (Investigation of Outcomes From Acute Coronary Syndrome) study (n=714) of patients with acute coronary syndromes. In INVEST, the haplotype comprising the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in whites (odds ratio [OR], 0.72; 95% CI, 0.57 to 0.92; P =0.0085) but not in blacks (OR, 1.21; 95% CI, 0.68 to 1.24; P =0.52) or Hispanics (OR, 0.96; 95% CI, 0.65 to 1.44; P =0.86). A less commonly reported linkage disequilibrium block was associated with worse prognosis in INVEST in both whites (OR, 1.52; 95% CI, 1.20 to 1.93; P =0.0006) and blacks (OR, 4.11; 95% CI, 1.55 to 10.88; P =0.004). Conclusions— Our findings suggest that previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported linkage disequilibrium block warrants further investigation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00133692.

Objectives The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of beta-adrenergic signaling. This study characterized single-nucleotide polymorphisms (SNPs) in the GRK2 gene (ADRBK1) and determined if these and a GRK5 Gln41Leu polymorphism affect the blood pressure (BP) response to atenolol or hydrochlorothiazide or adverse cardiovascular outcomes in hypertensives.Methods ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were tested for mRNA expression differences in 96 lymphoblastoid cell line samples and 12 leukocyte samples from hypertensives. BP response to atenolol and hydrochlorothiazide by ADRBK1 SNPs and GRK5 Gln41Leu was tested in 418 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses Study using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leu on death, myocardial infarction or stroke in treated hypertensives was evaluated in a case-control cohort (1:3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy using logistic regression models.Results A novel ADRBK1 promoter SNP was not associated with differential GRK2 expression. GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes independent of treatment strategy (adjusted odds ratio 0.535, 95% confidence interval: 0.313-0.951, P = 0.0222), but was not associated with BP response to antihypertensive medication. An ADRBK1 SNP (rs1894111 G>A) showed a signal for association with systolic and diastolic BP response to hydrochlorothiazide in Whites [ diastolic BP: -11.29 +/- 3.74 (G/A) versus -4.26 +/- 4.79 mmHg (G/G), P=0.0034 and systolic BP: -18.37 +/- 14.90 (G/A), -8.11 +/- 7.55 mmHg (G/G), P=0.0191].Conclusion The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives. Pharmacogenetics and Genomics 21:42-49 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

HomeCirculation: Cardiovascular GeneticsVol. 4, No. 4Response to Letter Regarding Article "Chromosome 9p21 Haplotypes and Prognosis in White and Black Patients With Coronary Artery Disease" Free AccessReplyPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Letter Regarding Article "Chromosome 9p21 Haplotypes and Prognosis in White and Black Patients With Coronary Artery Disease" Yan Gong, PhD Amber L. Beitelshees, PharmD, MPH Rhonda M. Cooper-DeHoff, PharmD Maximilian T. Lobmeyer, PhD and Taimour Y. Langaee, PhD Jun Wu, MD Sharon Cresci, MD Michael A. Province, PhD John A. Spertus, MD, MPH Carl J. Pepine, MD Julie A. Johnson, PharmD Yan GongYan Gong Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Gainesville, FL (Gong) Amber L. BeitelsheesAmber L. Beitelshees Division of Endocrinology, Diabetes and Nutrition University of Maryland School of Medicine Baltimore, MD (Beitelshees) Rhonda M. Cooper-DeHoffRhonda M. Cooper-DeHoff Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FL (Cooper-DeHoff) Maximilian T. LobmeyerMaximilian T. Lobmeyer Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Gainesville, FL (Lobmeyer, Langaee) and Taimour Y. LangaeeTaimour Y. Langaee Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Gainesville, FL (Lobmeyer, Langaee) Jun WuJun Wu Department of Genetics Division of Statistical Genomics Washington University School of Medicine St Louis, MO (Wu) Sharon CresciSharon Cresci Department of Medicine Cardiovascular Division Washington University School of Medicine St Louis, MO (Cresci) Michael A. ProvinceMichael A. Province Department of Genetics Division of Statistical Genomics Washington University School of Medicine St Louis, MO (Province) John A. SpertusJohn A. Spertus Mid America Heart Institute and University of Missouri Kansas City School of Medicine Kansas City, MO (Spertus) Carl J. PepineCarl J. Pepine Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FL (Pepine) Julie A. JohnsonJulie A. Johnson Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FL (Johnson) Originally published1 Aug 2011https://doi.org/10.1161/CIRCGENETICS.111.960807Circulation: Cardiovascular Genetics. 2011;4:e12We thank Dr Patel and colleagues for the very positive letter regarding our article on chromosome 9p21 and prognosis in patients with coronary artery disease.1 They observed findings similar to our data that the 9p21 locus (rs10757278) was not associated with risk of major adverse events in >2400 white patients, with a trend toward a protective effect.Patel et al suggested several potential explanations for why we did not observe an increased risk for the cardiovascular outcome with the widely reported risk allele for heart disease in 2 cohorts of patients with existing coronary artery disease. We agree that our cohort (mean age, 68.5 years) and theirs (mean age, 65 years) are older than most of the association studies of 9p21 and heart disease. According to a recent meta-analysis, 9p21 risk alleles are more strongly associated with incidence of heart disease in younger persons (odds ratio, 1.35) than in all persons combined (odds ratio, 1.21).2 We also agree that survival bias might play a role.Patel et al also suggested logical reasons why the risk allele for coronary artery disease/myocardial infarction (MI) might exhibit a trend for the protective effect relative to the adverse cardiovascular outcome. Specifically, they propose that those with prior MI are more aggressively treated, and this more-aggressive treatment with risk-reducing therapies (eg, statins, aspirin) might be leading to the reduced risk. To address these possibilities, we performed a stratified analysis based on history of MI and baseline use of statins or aspirin in our study population. Their suggestions do not appear to be supported by our data in INVEST (International Verapamil SR Trandolapril Study). The overall hazard ratio and 95% CI for each allele of rs10757278 was 0.81 (0.66 to 1.0, P=0.05); for patients with and without history of MI, the hazard ratios were almost identical (with MI, 0.79; 95% CI, 0.56 to 1.10; P=0.16; without MI, 0.80; 95% CI, 0.61 to 1.06; P=0.11). When the patients were stratified by use of lipid-lowering medications (yes or no), the hazard ratios also trended toward protection (taking lipid-lowering medication, 0.76; 95% CI, 0.56 to 1.03; not taking lipid-lowering medication, 0.86; 95% CI, 0.64 to 1.16). The results were similar when the analysis was stratified by aspirin use (taking aspirin, 0.89; 95% CI, 0.69 to 1.15; not taking aspirin, 0.63; 95% CI, 0.43 to 0.94).We appreciate the suggestions of Patel and colleagues to explain the chromosome 9p21 region as related to the risk of incidence of heart disease versus outcome of the disease. More studies are needed to understand the mechanisms by which these single-nucleotide polymorphisms modulate coronary artery disease pathogenesis, then we will be better able to assess how their effects may differ in disease initiation versus progression.Yan Gong, PhD Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Gainesville, FLAmber L. Beitelshees, PharmD, MPH Division of Endocrinology, Diabetes and Nutrition University of Maryland School of Medicine Baltimore, MDRhonda M. Cooper-DeHoff, PharmD Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FLMaximilian T. Lobmeyer, PhDTaimour Y. Langaee, PhD Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Gainesville, FLJun Wu, MD Department of Genetics Division of Statistical Genomics Washington University School of Medicine St Louis, MOSharon Cresci, MD Department of Medicine Cardiovascular Division Washington University School of Medicine St Louis, MOMichael A. Province, PhD Department of Genetics Division of Statistical Genomics Washington University School of Medicine St Louis, MOJohn A. Spertus, MD, MPH Mid America Heart Institute and University of Missouri Kansas City School of Medicine Kansas City, MOCarl J. Pepine, MD Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FLJulie A. Johnson, PharmD Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida College of Pharmacy Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FLDisclosuresDrs Cooper-DeHoff, Langaee, Pepine, and Johnson received grant funding from Abbott Laboratories. Drs Cooper-DeHoff and Pepine along with the University of Florida hold US Patent No. 5,991,731 related to INVEST. Dr Pepine has been a consultant for Abbott Laboratories.References1. Gong Y, Beitelshees AL, Cooper-DeHoff RM, Lobmeyer MT, Langaee TY, Wu J, Cresci S, Province MA, Spertus JA, Pepine CJ, Johnson JA. Chromosome 9p21 haplotypes and prognosis in white and black patients with coronary artery disease. Circ Cardiovasc Genet. 2011; 4:169–178.LinkGoogle Scholar2. Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010; 303:648–656.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 2011Vol 4, Issue 4 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.111.960807 Originally publishedAugust 1, 2011 PDF download Advertisement SubjectsClinical StudiesEpidemiologyGenetics

STK39 was earlier implicated as a hypertension susceptibility gene and is thought to be involved in the control of Na-Cl co-transporter activity. STK39 has been implicated as a putative thiazide diuretic response gene, as Na-Cl co-transporter activity is inhibited by thiazides. Thus, we aimed to determine whether STK39 is a thiazide response gene. One hundred and ninety-five 'good' and 194 'poor' responders to hydrochlorothiazide (HCTZ) were genotyped for approximately 100 single nucleotide polymorphisms (SNPs) within 5000 bases of STK39. SNPs meeting criteria for advancement to replication analysis (P<0.01), along with those earlier associated with hypertension, were then analyzed in a second population of 201 HCTZ-treated hypertensives. Two SNPs passed screening and were further analyzed. However, neither these, nor earlier implicated SNPs met criteria for significant association with blood pressure response to HCTZ. These data suggest that common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Background The alpha-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists.Methods The present study was conducted to prospectively investigate the relationship among the ADD 1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification.Results In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes.Conclusions In hypertensive patients with coronary artery disease, black ADD 1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

ABSTRACT During antibiotic drug development, media are frequently spiked with either serum/plasma or protein supplements to evaluate the effect of protein binding. Usually, previously reported serum or plasma protein binding values are applied in the analysis. The aim of this study was to evaluate this approach by experimentally measuring free, unbound concentrations for antibiotics with reportedly high protein binding and their corresponding antimicrobial activities in media containing commonly used protein supplements. Free, unbound ceftriaxone and ertapenem concentrations were determined in bacterial growth medium with and without bovine/human serum albumin, as well as adult bovine serum and human plasma using in vitro microdialysis. The corresponding antimicrobial activity was determined in MIC and time-kill curve experiments using Escherichia coli ATCC 25922 and Streptococcus pneumoniae ATCC 6303 as test strains. A semimechanistic maximum effect model was simultaneously fitted to the data and respective EC 50 (concentration at half-maximum effect) values compared. Protein binding differed significantly for ceftriaxone ( P < 0.05) between human plasma (76.8 ± 11.0%) and commercially available bovine (20.2 ± 8.3%) or human serum albumin (56.9 ± 16.6%). Similar results were obtained for ertapenem (human plasma, 73.8 ± 11.6%; bovine serum albumin, 12.4 ± 4.8%; human serum albumin, 17.8 ± 11.5%). The MICs and EC 50 s of both strains were significantly increased ( P < 0.05) for ceftriaxone when comparing human and bovine serum albumin, whereas the EC 50 s were not significantly different for ertapenem. Free, unbound antibiotic concentrations differed substantially between plasma and protein supplements and correlated well with antimicrobial efficacy. Therefore, free, active concentrations should be measured in the test system instead of correcting for literature protein binding values.