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1.  IMPACT OF TCF7L2 SINGLE NUCLEOTIDE POLYMORPHISMS ON HYDROCHLOROTHIAZIDE-INDUCED DIABETES 
Pharmacogenetics and genomics  2013;23(12):697-705.
OBJECTIVE
Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the Transcription Factor 7-Like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.
METHODS
We identified cases that developed NOD and age, gender, and race/ethnicity-matched controls from the INternational VErapamil SR Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP*hydrochlorothiazide treatment) interactions. Permuted interaction p values were corrected with the PACT test and adjusted for diabetes-related variables.
RESULTS
In INVEST whites, we observed three TCF7L2 SNPs with significant SNP*treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 (synergy index 3.37 [95%CI 1.72–6.59], p=5.0×10−4, PACT =0.03), which was associated with increased NOD risk in hydrochlorothiazide-treated patients (OR 1.53 [1.04–2.25], p=0.03) and decreased NOD risk in non hydrochlorothiazide-treated patients (OR 0.48 [0.27–0.86], p=0.02). The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association.
CONCLUSIONS
Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.
doi:10.1097/FPC.0000000000000012
PMCID: PMC3893755  PMID: 24128935
pharmacogenetics; TCF7L2; diabetes mellitus; hydrochlorothiazide
2.  Generic Drugs for Hypertension: Are They Really Equivalent? 
Current hypertension reports  2013;15(4):340-345.
Many antihypertensive drugs are now available in generic formulations at fractions of the cost of their branded counterparts. In the United States, marketing approval for generic medications is usually granted by the Food and Drug Administration on the basis of two simple studies involving dissolution rates and bioavailability in 24–36 healthy people, without data regarding antihypertensive efficacy, safety, or long-term outcomes. This process leaves many true disciples of “Evidence-Based Medicine” in a quandary: prescribe only brand-name medications that have been demonstrated in clinical trials to both lower blood pressure and prevent cardiovascular events, or instead recommend lower-priced generic agents that are usually supported by no such data. This review summarizes the current evidence that generic antihypertensive drugs are likely to be safe and effective, may increase the probability of medication availability and adherence for many patients, but by law, must have a different physical appearance than the original product.
doi:10.1007/s11906-013-0353-4
PMCID: PMC3715996  PMID: 23700299
Generic medications; hypertension; blood pressure control; bioequivalence; thiazide diuretics; beta-blockers; calcium antagonists; angiotensin converting enzyme inhibitors; angiotensin receptor blockers
3.  Thiazide Induced Dysglycemia – It's Time To Take Notice 
doi:10.1586/14779072.6.10.1291
PMCID: PMC3891644  PMID: 19018679
4.  Antihypertensive Drug Class Interactions and Risk for Incident Diabetes: A Nested Case–Control Study 
Background
We aimed to determine how single and combination antihypertensive therapy alters risk for diabetes mellitus (DM).Thiazide diuretics (TD), β blockers (BB), and renin–angiotensin system blockers (RASB) impact DM risk while calcium channel blockers (CCB) are neutral. DM risk associated with combinations is unclear.
Methods and Results
We enrolled nondiabetic patients from Kaiser Permanente Northwest with a fasting plasma glucose (FPG) <126 mg/dL between 1997 and 2010. DM cases were defined by a FPG ≥126 mg/dL, random plasma glucose ≥200 mg/dL, HbA1c ≥7.0%, or new DM prescription (index date). We used incidence density sampling to match 10 controls per case on the date of follow‐up glucose test (to reduce detection bias), in addition to age and date of cohort entry. Exposure to antihypertensive class was assessed during the 30 days prior to index date. Our cohort contained 134 967 patients and had 412 604 glucose tests eligible for matching. A total of 9097 DM cases were matched to 90 495 controls (median age 51 years). Exposure to TD (OR 1.54, 95% CI 1.41 to 1.68) or BB (OR 1.19, 95% CI 1.11 to 1.28) was associated with an increased DM risk, while CCB and RASB exposure was not. TD+BB combination resulted in the fully combined diabetogenic risk of both agents (OR 1.99, 95% CI 1.80 to 2.20; interaction OR 1.09, 95% CI 0.97 to 1.22). In contrast, combination of RASB with either TD or BB showed significant negative interactions, resulting in a smaller DM risk than TD or BB monotherapy.
Conclusions
Diabetogenic potential of combination therapy should be considered when prescribing antihypertensive therapy.
doi:10.1161/JAHA.113.000125
PMCID: PMC3698771  PMID: 23752710
β blockers; diabetes; diabetogenic; drug interactions; hypertension; RAS blockers; thiazide diuretics
5.  IMPACT OF ABDOMINAL OBESITY ON INCIDENCE OF ADVERSE METABOLIC EFFECTS ASSOCIATED WITH ANTIHYPERTENSIVE MEDICATIONS 
Hypertension  2009;55(1):61-68.
We assessed adverse metabolic effects (AMEs) of atenolol and hydrochlorothiazide (HCTZ) among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes. Intervention included randomization to HCTZ 25mg or atenolol 100mg monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, HDL cholesterol and uric acid were measured at baseline and after mono-and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose ≥ 100mg/dl (impaired fasting glucose [IFG]), triglyceride ≥ 150 mg/dl, HDL ≤ 40mg/dl for men or ≤ 50mg/dl for women, or new onset diabetes according to presence or absence of abdominal obesity. Abdominal obesity was present in 167/395 (58%). Regardless of strategy, in those with abdominal obesity, 20% had IFG at baseline compared with 40% at end of study (p<0.0001). Proportion with triglycerides ≥ 150 mg/dl increased from 33% at baseline to 46% at end of study (p<0.01). New onset diabetes occurred in 13 (6%) with and in 4 (2%) without abdominal obesity. Baseline levels of glucose, triglyceride and HDL predicted adverse outcomes and predictors for new onset diabetes after monotherapy in those with abdominal obesity included HCTZ strategy (OR 47, 95% CI 2.55-862), female sex (OR 31.3, 95% CI 2.10-500) and uric acid (OR 3.2, 95% CI 2.35-7.50). Development of AME, including new onset diabetes associated with short term exposure to HCTZ and atenolol was more common in those with abdominal obesity.
doi:10.1161/HYPERTENSIONAHA.109.139592
PMCID: PMC2811061  PMID: 19917874
atenolol; hydrochlorothiazide; abdominal obesity; metabolic syndrome; new onset diabetes; hypertension
6.  Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients With Diabetes and Coronary Artery Disease 
Context
Hypertension guidelines advocate treating systolic blood pressure (BP) to less than 130 mm Hg for patients with diabetes mellitus; however, data are lacking for the growing population who also have coronary artery disease (CAD).
Objective
To determine the association of systolic BP control achieved and adverse cardiovascular outcomes in a cohort of patients with diabetes and CAD.
Design, Setting, and Patients
Observational subgroup analysis of 6400 of the 22 576 participants in the International Verapamil SR-Trandolapril Study (INVEST). For this analysis, participants were at least 50 years old and had diabetes and CAD. Participants were recruited between September 1997 and December 2000 from 862 sites in 14 countries and were followed up through March 2003 with an extended follow-up through August 2008 through the National Death Index for US participants.
Intervention
Patients received first-line treatment of either a calcium antagonist or β-blocker followed by angiotensin-converting enzyme inhibitor, a diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at less than 130 mm Hg; usual control if it ranged from 130 mm Hg to less than 140 mm Hg; and uncontrolled if it was 140 mm Hg or higher.
Main Outcome Measures
Adverse cardiovascular outcomes, including the primary outcomes which was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke.
Results
During 16 893 patient-years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25–1.71; P<.001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93–1.32; P=.24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99–1.45; P=.06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01–1.32; P=.04).
Conclusion
Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control.
doi:10.1001/jama.2010.884
PMCID: PMC3008411  PMID: 20606150
8.  Cardiovascular Therapies and Associated Glucose Homeostasis: Implications across the Dysglycemia Continuum 
Certain cardiovascular drugs have adverse effects on glucose homeostasis which may lead to important long-term implications for increased risks for adverse outcomes. Thiazide diuretics, niacin, and β-adrenergic blockers impair glucose homeostasis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated beneficial metabolic effects. The newer vasodilating β-blocking agents and calcium antagonists appear to be metabolically neutral. These considerations, in addition to meticulous attention to blood pressure control and lifestyle changes, have the potential to beneficially modify glycemia and long-term risks. These considerations have particular importance in younger patients who may also have prediabetes or the metabolic syndrome and who are likely to require therapy over the course of decades.
doi:10.1016/j.jacc.2008.10.037
PMCID: PMC2655143  PMID: 19179214
metabolic syndrome; prediabetes; thiazide diuretic; dysglycemia; glucose homeostasis
9.  INVEST Revisited: A Review of Findings from the INternational VErapamil SR-Trandolapril STudy (INVEST) 
Summary
The INternational VErapamil SR-Trandolapril STudy (INVEST), a randomized trial of 22,576 predominantly elderly patients with an average 2.7-year follow-up, compared a calcium antagonist led strategy (verapamil SR plus trandolapril) with a β blocker led strategy (atenolol plus hydrochlorothiazide) for hypertension treatment and prevention of cardiovascular outcomes in coronary artery disease. patients.
Patients received individualized dose and drug titration following a flexible, multi-drug, guideline-based treatment algorithm, with the objective of achieving optimal blood pressure (BP) control individualized for comorbidities (e.g., diabetes). The primary outcome (PO) was first occurrence of death (all-cause), nonfatal myocardial infarction or nonfatal stroke.
The strategies resulted in significant and very similar BP reduction with approximately 70% of patients in both strategies achieving BP control (< 140/90 mm Hg). Increasing number of office visits with BP in control was associated with reduced risk of the PO. Overall, there was no difference in the PO comparing the strategies, however new onset diabetes occurred more frequently in those assigned the atenolol strategy. This report summarizes findings from INVEST and puts them in perspective with our current state of knowledge derived from other large hypertension treatment trials. INVEST findings support that 1) BP reduction is important for prevention of adverse cardiovascular morbidity and mortality; and 2) selection of antihypertensive agents should be based on patient comorbidities and other risk factors (e.g. risk for diabetes) and not necessarily that any one drug be given to all.
doi:10.1586/erc.09.102
PMCID: PMC2800790  PMID: 19900016
Coronary artery disease; hypertension; atenolol; verapamil SR; trandolapril; hydrochlorothiazide; INVEST; new onset diabetes
10.  Antihypertensive Medications: Benefits of BP Lowering and Hazards of Metabolic Effects 
Blood pressure reduction is associated with significant reduction in adverse cardiovascular outcomes. Certain blood pressure lowering drugs have adverse effects on glucose homeostasis, and have been associated with development of both pre-diabetes and diabetes during use. There is controversy over the significance of diabetes that develops during treatment with antihypertensives and whether the benefits of blood pressure reduction offset the hazards of dysglycemia that can lead to diabetes. Many hypertension treatment guidelines have recently undergone revisions to include consideration for the metabolic effects of antihypertensive drugs, particularly in high risk populations. This review summarizes the data related to the benefits of blood pressure reduction as well as the adverse metabolic effects and new onset diabetes associated with some antihypertensive medications.
doi:10.1586/erc.09.31
PMCID: PMC2799117  PMID: 19505284
Hypertension; Diabetes; Pre Diabetes; Thiazide Diuretics; β blockers; New Onset Diabetes; Cardiovascular Outcomes
11.  Metabolic Syndrome and Cardiovascular Disease: Challenges and Opportunities 
Clinical cardiology  2007;30(12):593-597.
Summary
Metabolic syndrome (MetS) has been defined in different ways. However, key components common to most definitions are a constellation of risk factors including abdominal adiposity, impaired fasting glucose, hypertension, and dyslipidemia. A major mediator of MetS appears to be insulin resistance, which relates to the development of the vascular and metabolic dysfunctions that precede overt cardiovascular disease and type 2 diabetes. Evidence suggests that the mechanisms underlying the elevated cardiovascular risk associated with MetS begin with subclinical organ damage. Therapy for MetS targets individual components of the syndrome and includes lifestyle interventions, lipid-modifying therapy, and antihypertensive agents, particularly those that inhibit the renin-angiotensin system. Results of trials of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated reductions in new-onset diabetes and cardiovascular events in a wide range of patients. Clinical trials to investigate further the role of these drugs in the primary prevention of type 2 diabetes in patients with MetS are currently under way. The purpose of this paper is to review the MetS from the perspective of the cardiology workforce with the hope that a better understanding of the links between MetS and cardiovascular disease could lead to improved management of persons at risk.
doi:10.1002/clc.7
PMCID: PMC2794411  PMID: 17607758
renin-angiotensin system; angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; cardiovascular disease; insulin resistance; metabolic syndrome; type 2 diabetes mellitus
12.  The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update 
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding SNP, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for SLCO1B1 and simvastatin-induced myopathy.
doi:10.1038/clpt.2014.125
PMCID: PMC4169720  PMID: 24918167
pharmacogenetics; pharmacogenomics; myalgias; rhabdomyolysis; CPIC; SLCO1B1; simvastatin
13.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
14.  Mortality implications of angina and blood pressure in hypertensive patients with coronary artery disease: new data from extended follow-up of the INternational VErapamil/Trandolapril STudy (INVEST) 
Clinical cardiology  2013;36(8):442-447.
Background
Angina and hypertension are common in patients with coronary artery disease (CAD), however the effect on mortality is unclear. We conducted this prespecified analysis of the INternational VErapamil/Trandolapril STudy (INVEST) to assess relationships between angina, blood pressure (BP), and mortality among elderly, hypertensive CAD patients.
Hypothesis
Angina and elevated BP will be associated with higher mortality.
Methods and Results
Extended follow-up was performed using the National Death Index for INVEST patients in the United States (n=16,951). Based on angina history at enrollment and during follow-up visits, patients were divided into groups: persistent (n=7184), new onset (n=899), resolved (n=4070), or never (n=4798). BP was evaluated at baseline, during drug titration and during follow-up on-treatment. On-treatment systolic BP was classified as tightly controlled (<130 mmHg), controlled (130–139 mmHg), or uncontrolled (≥140 mmHg). A Cox proportional hazards model was created adjusting for age, heart failure, diabetes, renal impairment, myocardial infarction, stroke, and smoking. The angina groups and BP control groups were compared using the never angina group as the reference. Only in the persistent angina group was a significant association with mortality observed, with an apparent protective effect (HR 0.82, 95% CI 0.75 to 0.89, P <0.0001). Uncontrolled BP was associated with increased mortality risk (HR 1.29, 95% CI 1.20 to 1.40, P <0.0001), as were several other known cardiovascular risk factors.
Conclusions
In hypertensive CAD patients, persistent angina was associated with lower mortality. The observed effect was small compared with other cardiovascular risk factors, such as BP, which were associated with increased mortality.
doi:10.1002/clc.22145
PMCID: PMC3775918  PMID: 23720247
Angina; Hypertension; Coronary disease; Prognosis; Myocardial infarction
15.  Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide 
Hypertension  2013;62(2):391-397.
To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses Study (N=228) and the Genetic Epidemiology of Responses to Antihypertensive Study (N=196). Polymorphisms associated with blood pressure response at p<10-5 were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, alpha replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem Study (N=420) and the Genetics of Drug Responsiveness in Essential Hypertension Study (N=206), and the combined four-study meta-analysis p-value achieved genome-wide significance (p=3.3 × 10-8). Systolic/diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (4/4 mmHg greater) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem Study, and the combined three-study meta-analysis p-value approached genome-wide significance (p=5.5 × 10-8). The findings document clinically-important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.
doi:10.1161/HYPERTENSIONAHA.111.00436
PMCID: PMC3780966  PMID: 23753411
Hypertension; high blood pressure; antihypertensive therapy/diuretics; hydrochlorothiazide; genomics; pharmacogenomics; protein kinase C
16.  PHARMACOGENOMIC ASSOCIATION OF NON-SYNONYMOUS SNPS IN SIGLEC12, A1BG AND THE SELECTIN REGION AND CARDIOVASCULAR OUTCOMES 
Hypertension  2013;62(1):48-54.
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.
doi:10.1161/HYPERTENSIONAHA.111.00823
PMCID: PMC3686553  PMID: 23690342
Pharmacogenomics; Hypertension; antihypertensive agents; cardiovascular outcomes; genetic variation; beta-blockers, calcium channel blockers
17.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessic A. | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(8):1663-1678.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
doi:10.1093/hmg/dds555
PMCID: PMC3657476  PMID: 23303523
18.  Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics 
Journal of hypertension  2013;31(4):698-704.
Objective
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.
Methods
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.
Results
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)].
Conclusion
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.
doi:10.1097/HJH.0b013e32835e2a71
PMCID: PMC3756535  PMID: 23353631
epithelial sodium channel; hypertension; International Verapamil SR Trandolapril Study; neural precursor cell expressed developmentally down-regulated 4 like; Pharmacogenomic Evaluation of Antihypertensive Responses; pharmacogenetics
19.  Cardiovascular and Mortality Risk of Apparent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Report From the NHLBI‐Sponsored WISE Study 
Background
Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (WISE) analysis, we assessed long‐term adverse outcomes associated with apparent treatment‐resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography.
Methods and Results
Women (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow‐up. Apparent treatment‐resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow‐up. Risk of all‐cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension.
Conclusions
In this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long‐term risk of major adverse events, including death, that emerged early during follow‐up.
doi:10.1161/JAHA.113.000660
PMCID: PMC3959684  PMID: 24584740
hypertension; resistant hypertension; WISE; women
20.  Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives – Results from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study 
Background
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.
Conclusions
These findings suggest selected signals from hypertension GWAS may predict BP response to atenolol and HCTZ when assessed through risk scoring.
doi:10.1161/CIRCGENETICS.112.964080
PMCID: PMC3529147  PMID: 23087401
beta-blocker; diuretics; hypertension; pharmacogenetics; polymorphisms blood pressure
21.  Association of Chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression 
The pharmacogenomics journal  2012;13(3):257-263.
A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and hydrochlorothiazide response in an independent sample of 746 Caucasians and African-Americans randomized to hydrochlorothiazide or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4mmHg, P=0.0275; diastolic: 2.5mmHg, P=0.0196) responses to hydrochlorothiazide vs. T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as hydrochlorothiazide-specific. Expression analyses in hydrochlorothiazide-treated African-Americans showed differential leukocyte YEATS4 expression between rs7297610 genotype groups at baseline (P=0.024), and reduced expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.
doi:10.1038/tpj.2012.4
PMCID: PMC3360116  PMID: 22350108
hydrochlorothiazide; hypertension; pharmacogenomics; blood pressure; YEATS4; diuretics
22.  Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study 
PLoS ONE  2013;8(10):e76984.
We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.
doi:10.1371/journal.pone.0076984
PMCID: PMC3792156  PMID: 24116192
23.  G PROTEIN RECEPTOR KINASE 4 (GRK4) POLYMORPHISMS: BETA-BLOCKER PHARMACOGENETICS AND TREATMENT RELATED OUTCOMES IN HYPERTENSION 
Hypertension  2012;60(4):957-964.
G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized three nonsynonymous GRK4 SNPs, R65L (rs2960306), A142V (rs1024323) and A486V (rs1801058) would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long term cardiovascular outcomes (all cause, death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 SNPs were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In Caucasians and African Americans, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1 ± 6.8 vs −6.8 ± 7.1 vs −5.3 ± 6.4 mmHg in participants with 0, 1 and 2 copies of 65L-142V respectively; p=0.0088). 1460 participants with hypertension and coronary artery disease from the INternational VErapamil SR / Trandolapril STudy (INVEST) were genotyped and variant alleles of all three GRK4 SNPs were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (Odds ratio 2.29 [1.48–3.55], p=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R-homozygotes, suggesting a potential interaction between these two genes.
doi:10.1161/HYPERTENSIONAHA.112.198721
PMCID: PMC3462355  PMID: 22949529
hypertension; GRK4; atenolol; beta-blocker; outcomes; ADRB1; pharmacogenetics
24.  Simple Integer Risk Score to Determine Prognosis of Patients With Hypertension and Chronic Stable Coronary Artery Disease 
Background
It is difficult to accurately determine prognosis of patients with hypertension and chronic stable coronary artery disease (CAD). Our aim was to construct a risk score for predicting important adverse events in this population.
Methods and Results
Patients with hypertension and chronic stable CAD enrolled in the INternational VErapamil‐SR/Trandolapril STudy (INVEST) comprised the study cohort. Candidate predictor variables were obtained from patients with at least 1 postbaseline visit. Patients were divided into development (n=18 484) and validation cohorts (n=2054). Cox regression model identified predictors of the primary outcome: all‐cause mortality, myocardial infarction, or stroke at a mean follow‐up of 2.3 years. The hazard ratio of each variable was rounded to the nearest integer to construct score weights. A score 0 to 4 defined low‐risk, 5 to 6 intermediate‐risk and ≥7 high‐risk. The following variables were retained in the final model: age, residence, body mass index, on‐treatment heart rate and BP, prior myocardial infarction, heart failure, stroke/transient ischemic attack, smoking, diabetes, peripheral arterial disease, and chronic kidney disease. The primary outcome occurred in 2.9% of the low‐risk group, 6.5% of the intermediate‐risk group, and 18.0% of the high‐risk group (P for trend <0.0001). The model was good at discriminating those who had an event versus those who did not (C‐statistic=0.75). The model performed well in a validation cohort (C‐statistic=0.77).
Conclusion
Readily available clinical variables can rapidly stratify patients with hypertension and chronic stable CAD into useful risk categories.
doi:10.1161/JAHA.113.000205
PMCID: PMC3828777  PMID: 23948642
clinical decision rule; coronary artery disease; coronary heart disease; ischemic heart diseae; prognosis; risk score
25.  Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment 
PLoS ONE  2013;8(3):e57639.
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.
doi:10.1371/journal.pone.0057639
PMCID: PMC3594230  PMID: 23536766

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