International Consortium for Antihypertensives Pharmacogenomics Studies

The ACCORD trial was a randomized, multicenter, double 2 x 2 factorial design clinical trial which tested the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality in middle-aged and older white, black, asian, or Hispanic participants with type 2 diabetes mellitus who are at high risk for CVD events. All participants (n=10,251) were in the glycemia trial which tested the hypothesis that therapy targeting a HbA1c of <6% will reduce the rate of CVD events more than a target of an HbA1c of 7.0-7.0%. The study then tested two other hypotheses in the context of good glycemic control; The lipid trial tested therapy using a fibrate plus a statin versus statin plus placebo, the blood pressure trial tested the therapeutic strategy targeting a SBP <120 mm Hg compared to a target of <140 mm Hg. The primary end point for all three research questions was first occurrence to a major CVD event (nonfatal MI, nonfatal stroke, or CVD death). There are over 8,000 ACCORD participants who gave consent for genetic research and for whom DNA samples are available.
The ACCORD trial found that the more intense arm of HbA1c lowering increased mortality and did not reduce major CVD events which led to an early termination of the more intense glycemic control arm and participants were transitioned to standard therapy.
The ACCORD BP trial found no conclusive evidence that an intense BP control strategy reduced rate of CVD events.
The ACCORD lipid trial found that combination of fenofibrate and simvastatin compared to simvastatin alone did not reduce CVD events.

After a run-in period of 8 weeks under standardized dietary regimen and complete diagnostic workout to confirm the presence of the disease and to exclude secondary hypertension, BP response to Ramipril 5mg/day was evaluated after 4 and 8 weeks of treatment: side effects were recorded. All patients were never treated mild-to-moderate essential hypertensive younger than 60 years and without any concurrent disease. A cohort of 411 patients was studied.
Long term follow-up: ongoing.
Cardiac (ECHO), renal, metabolic phenotypes available.
Serum, plasma, and urine samples are available.
The primary CV outcome was combined CV/cerebrovascular events while secondary outcomes were atrial fibrillation, CKD, new onset of diabetes.

GenHAT is an ancillary study to ALLHAT, which included 39,114 high-risk hypertensive participants with at least one other CVD risk factor age 55+ who were ethnically diverse. GenHAT aimed to determine if variants in hypertension-related genes interacted with type of antihypertensive drug to modify risk of CHD. Participants were randomized to one of four treatment groups: chlorthalidone 12.5-25 mg, amlodipine 2.5-10 mg, lisinopril 10-40 mg and doxazosin 2-8 mg; mean follow-up was 4.9 years. The main outcome was fatal CHD and nonfatal MI with secondary outcomes of individual and combined CVD. Secondary outcomes were all-cause mortality, combined CHD (CHD, coronary revascularization, or hospitalized angina), stroke, combined CVD (combined CHD, stroke, treated but not hospitalized angina, heart failure, or peripheral arterial disease), and end-stage renal disease. GenHAT initially set out to genotype 6 candidate genes (more were typed later) including ACE I/D. For the ACE I/D, GenHAT did not identify elevated risk for the DD genotype compared with ID and II for primary and secondary outcomes. No evidence was found to support the hypothesis that the ACE I/D genotype might influence the reduction in BP achieved with an ACEI compared with other commonly used medications.

ASCOT was a randomized multicenter clinical trial including individuals from the UK, Ireland and Scandinavia. 19,342 hypertensive patients aged 40-79 years with at least three other CV risk factors were randomized to one of two antihypertensive regimens, an amlodipine 5 mg-based regimen or atenolol 5 mg-based regimen. Participants with non-fasting total cholesterol concentrations 6.5 mmol/L or less formed the lipid-lowering arm and either received atorvastatin 10 mg or placebo in addition to antihypertensive regimen.
They found that the amlodipine-based regimen prevented cardiovascular events and induced less diabetes then the atenolol-based regimen as well as reduction in major cardiovascular events with atorvastatin.
Glucose, total cholesterol, LDL, HDL, TG, potassium, sodium, creatinine and blood pressure measurements are available at baseline and follow up.
There are 21 sub-studies, and these sub-study protocols are published in the Journal of Human Hypertension. (J. Hum. Hypertens. (2001) 15, suppl 1).

BB-SS was an open label study conducted in Sardinia, Italy: 433 participants with untreated hypertension (>140/90) younger than 60 years and without any concurrent disease were included and genotyped (GWAS). Participants received study drug atenolol 50+50 mg.
First follow up visit after 4 weeks: if no side effects and BP was <140/90 continue treatment but if no side effects and BP was still greater than 140/90 they received add HCTZ 25mg, if heart rate was (HR) < 50 and no side effects reduce atenolol from 50+50 to 25+25 mg.
Second follow up visit after 3-4 months of treatment: if BP was < 140/90 continue atenolol+HCTZ otherwise if BP was ≥ 140/90 add amlodipine 5mg.
Third follow up visit after 8 months complete treatment.
Overall: if HR<50 reduce atenolol to 25+25mg, if HR <50 after dose reduction suspend.
Monitored serum K+ when HCTZ in regimen.
Long term follow-up: ongoing.
Cardiac (ECHO), renal, metabolic phenotypes available. Serum, plasma, and urine samples are available. The primary CV outcome was combined CV/cerebrovascular events while secondary outcomes were atrial fibrillation, CKD, new onset of diabetes.

The CHARGE consortium was formed to facilitate genome-wide association study (GWAS) meta-analyses and replication opportunities among large population-based cohort studies. The CHARGE consortium has expanded from the five original prospective cohort studies from the US and Europe to ten and coordinates the efforts of more than 40 working groups, including a working group on pharmacogenetics. The consortium aims to identify genetic determinants of risk factors, subclinical-disease measures, and clinical events. A genome-wide association study of blood pressure identified sixteen novel loci, ten of which provide new clues to blood pressure physiology. Findings so far provide new insights into the genetics and biology of blood pressure.

CHIEF was a multicenter randomized controlled clinical trial that compared the efficacy of amlodipine plus angiotensin II receptor blocker with amlodipine plus diuretics on reducing cardiovascular events in high-risk Chinese hypertensive patients aged 50-79. Regimens were titrated to achieve various blood pressure goals that differed for the general population, diabetes, or the elderly. The authors determined that both combination regimens were effective and safe for high-risk hypertensive patients.

The Campania Salute Network (CSN) was formed to improve the process of care for patients with hypertension by integrating general practitioners and specialists. The system includes over 25.000 southern Italians and is an integrated environment which uses computer technology and web access to the clinical data in order to test the effectiveness on BP and total cardiovascular risk (TCVR) control. Clinical data of patients of an average follow up of 15 years including serum biochemistry (kidney function, lipid profile, glucose metabolism, and BC count) as well as cardiac and carotid ultrasound. About 1000 genomic DNA from patients of the CNS have been sequenced. A series of evidences have been reported using this database, including that CSN provided a larger BP reduction and TCVR score as compared to control whom were outside of the network, DM incidence in relation to statin prescription was also looked at and found that statin prescription for primary prevention is not associated with increased risk of incident DM,
Beta adrenergic receptor variants predict LVH development, LVH reduction after treatment, insurgence of dyslipidemia after beta blockade treatment.

The Estonian biobank cohort participants represent a large proportion of the Estonian adult population (5%), making it ideal for population-based studies. Baseline health examinations, blood samples, white blood cells, and plasma tests, as well as a questionnaire on health-related topics are available. A significant portion of the cohort has whole genome sequencing, SNP data, and/or NMR metabolome data available. The data is continuously updated and some participants have been re-contacted for follow-up purposes and resampling. The Estonian Genome Center of the University of Tartu is actively collaborating with other universities and research institutes and encourages fellow scientists worldwide to co-initiate new projects.

FEVER was a prospective multicenter double-blind randomized parallel group trial conducted in Chinese patients aged 50-79 with one or two additional CV risk factors whose SBP was between 140-180 mmHg and DBP 90-100 mmHg 6 weeks after switching from their previous antihypertensive therapy to 12.5 mg of HCTZ. Participants were then randomized to receive felodipine ER or placebo to compare the incidence of stroke and other CV events for 24 months. The authors found that stroke and other CV events were significantly reduced in the felodipine group. DNA samples are available for 600 participants.

GENRES is a prospective, single center, randomized, double-blind, cross-over, placebo-controlled clinical trial conducted in 237 moderately hypertensive Finnish men aged 35 to 60 years. Four antihypertensive drugs from four different classes were given to each participant as monotherapy for 4 weeks in a random order, with a placebo washout before and between the treatment periods (hydrochlorothiazide 25mg, bisoprolol 5mg, amlodipine 5mg, and losartan 50 mg). Responses were assessed with 24-h ambulatory and office blood pressure measurements and analyzed according to clinical parameters (e.g. age, BMI, duration of hypertension, etc).
Baseline clinical and laboratory parameters could to some extent be used to predict the efficacy of antihypertensive therapies. Accordingly, a negative correlation was found between total serum calcium concentration and blood pressure response to amlodipine, while plasma renin activity correlated positively with blood pressure response to losartan and bisoprolol but negatively with response to hydrochlorothiazide. Data on plasma glucose, insulin, total cholesterol, LDL, HDL, triglyceride, uric acid, potassium, sodium, creatinine, aldosterone and renin levels are all available for further studies.
This trial should provide an excellent platform for future pharmacogenetic analyses on antihypertensive drug responsiveness. Initial GWAS studies, supplemented with data from other ICAPS groups, provide evidence for a variant in the nephrin gene influencing losartan response and two other gene loci (ALDH1A3, CLIC5) influencing hydrochlorothiazide response.

GERA1 was a prospective interventional trial of hydrochlorothiazide in 600 participants to find predictors of BP response and estimate how much inter-individual variation could be explained by the predictors in a biracial (African American & Caucasian) sample aged 18-60 with essential hypertension. Participants withdrew from antihypertensive medications for at least four weeks, were stabilized on a standardized sodium diet and then were treated with HCTZ 25 mg for four weeks. RAAS activity, glucose, total cholesterol, HDL, triglyceride, uric acid, potassium, sodium, and creatinine were measured at enrollment, baseline, and end of treatment. Black race and female gender were associated with greater BP reduction, and combining the effects of all identified predictors accounted for 38% of inter-individual variation in SBP and 20% of DBP response. The systematic search revealed numerous predictors of BP response to the standard dose of HCTZ but the majority of variation remained unexplained.

GERA 2 was a prospective interventional trial of candesartan in 600 participants to find predictors of BP response and estimate how much inter-individual variation could be explained by the predictors in a biracial (African American & Caucasian) sample aged 18-60 with essential hypertension. Following a four-week washout period, participants were treated with candesartan 16 mg/day for two weeks followed by 32 mg/day for 4 additional weeks Measurements were done at enrollment, baseline, and at the end of treatment. Samples included glucose, total cholesterol, HDL, triglyceride, potassium, sodium, creatinine, and plasma renin activity. The investigators found that found combined effects of non-genetic predictors accounted for 39% of the inter-individual variation in SBP and 33% of DBP with candesartan.

GoDARTS has created a high quality resource with 17000 recruitment of consented patients with type 2 diabetes and matching controls throughout Tayside region in Scotland, UK that is readily available to researchers worldwide to help define genetic factors related to diabetes. All EMR information is available including lab values. The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as type 2 diabetes susceptibility locus and two common variants (rs12255372 and rs7903146) were investigated using the Tayside population. Both variants were associated with type 2 diabetes, and a gene dosage effect of the rare allele of both variants were observed, with the TT homozygote having a greater risk compared to hertozygote CT. It was also observed that males displayed a higher degree of genotype-associated risk compared to females and that the T allele was associated with increased HbA1c levels in both cases and controls. This large case-control study confirms TCF7L2 to be a diabetes locus and suggests that variants may be associated with increased disease severity and therapeutic failure.

SHARE is a initiative to establish a register of people living in Scotland to provide secure access to their health records which will help with developing new treatments and cures for heart disease. GoSHARE is a sub-study of SHARE where investigators are asking to store and use blood that remains after routine clinical testing. GoSHARE register will allow for research with the relationship of genes, disease, and response to treatment. All EMR information is available, but stored serum is not currently being done.
A European-wide study led by the University of Dundee is set to identify reliable biomarkers which can predict side effects of statins and ACEI and then be developed into a commercially available test, they currently have 10% of the population of Tayside, ages 16 and older, and the hope is through the GoSHARE initiative everyone in Tayside will take part.

GS-SFHS is a family-based genetic epidemiology study with DNA, socio-demographic and clinical data from about 24,000 volunteers across Scotland aged 18-98. The data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Important features of GS-SFHS include the family-based recruitment, the depth of phenotype information, consent for linkage of all data to comprehensive routine health-care records, and broad consent to use their data and samples for a wide range of medical research with re-contact potential for collection of other data or samples. DNA was collected via blood and saliva; whole blood, serum, urine, cryopreserved bloods for lymphocytes are available and other lab data is only through linkage. These features were designed to maximize the resource to identify, replicate, or control for genetic factor associated with a wide spectrum of illnesses and risk factors both now and in the future.

HARP is one of two Pharmacogenetics and Risk of cardiovascular (PARC) Disease Studies funded by the National Institutes of Health (Bethesda, MD) which was a pilot prospective clinical trial that examined genotypic polymorphisms that might account for differential antihypertensive effects of ACEI among Caucasians and African American.. Currently phenotypic predictors of BP response are available and genetic predictors will be reported in the future. 189 participants were 18 years and older, self-identified their race, and could not have been on antihypertensive medication in the month before enrollment. They received a fixed dose of 10mg ramipril for 8 weeks. Office and ambulatory blood-pressure were measured to compare daytime and nighttime response in both races. The authors found that African Americans had a higher prevalence of nondipping 24-h BP pattern compared to Caucasians while ramipril was more effective overall in lowering daytime blood pressure in Caucasian compared to African Americans. Potassium, sodium, creatinine, aldosterone, ACE activity, and microalbuminuria are available from baseline and follow up.

IDEAL was a crossover, double-blind, placebo-controlled trial that aimed to identify phenotypic, genetic, or environmental markers of BP response to ACEIs and diuretics in 112 white French participants. Mild hypertensive participants were aged 25-70 with no previous treatment of hypertension and received successively in a random order Indapamide 1.5 mg and Perindopril 8 mg for 4 weeks each, during periods separated by 4 weeks of placebo. Clinic/ office BP was taken after each 4 week regimen. Glucose, total cholesterol, LDL, HDL, TG, uric acid, potassium, sodium, creatinine, plasma renin activity, aldosterone, and CRP are available from baseline and creatinine, plasma renin activity, aldosterone, and CRP are available from follow up. Results are expected to improve knowledge in drug’s mechanisms and pathophysiology of hypertension in order to personalize treatment.

In Mexico, hypertension prevalence is around 30%. However, patients over 65 years old show a prevalence up to 64%. There are several risk factors for developing hypertension, including body weight, diet, exercise, alcoholism, smoking, age, and genetics.
A recent study conducted in government hospitals in Mexico City, (Mexican Institute for Social Security [IMSS]) revealed that 70% of antihypertensive drugs prescribed are represented by ACE inhibitors, angiotensin II receptor blockers, and calcium channel blockers. The Federal Commission for the Protection against Sanitary Risk (COFEPRIS), an agency comparable to the FDA, has over 60 antihypertensive drugs approved for use in Mexico. Yet, approximately 50% of patients under treatment cannot control their blood pressure levels, and are prescribed different antihypertensive drugs using the trial and error approach.
We hypothesize that the identification of pharmacogenetic variants associated with drug response and safety may aid to expedite drug selection for initial treatment after hypertension diagnosis.
Recent studies have shown that Mestizos (Mexican people of mixed decent) from Mexico have significant allele frequency differences for known relevant pharmacogenetic variants and novel variants that are prevalent in this geographical region.
PHEM is a population-based, prospective, interventional trial of 500 Mestizos > 60 years old diagnosed with essential hypertension on ACE inhibitors, angiotensin II receptor blockers or calcium channel blockers. Our aim is to investigate pharmacogenetic variation, and pinpoint potential markers in these patients.
We have completed recruitment of 500 patients under treatment and extracted DNA from a blood sample. Genotyping will be performed using a custom GSA-Illumina which includes 300 AIMS for Mexican Populations.

INVEST was an international, randomized, open label, blinded end point study clinical trial of 22,576 hypertensive CAD patients ages 50 and older with CHD and essential hypertension. Patients were randomized to either a calcium antagonist led treatment strategy (verapamil SR 240/360 mg) or a beta blocker led treatment strategy (atenolol 50/100 mg) and also received trandolapril and/or HCTZ as needed to achieve BP control. Mortality and morbidity outcomes were measured at 24 months and no difference was found for the primary outcome comparing the treatment strategies. DNA samples are available for 5,979 of the patients.
Primary outcome: first occurrence of all-cause death, nonfatal MI, or nonfatal stroke
Secondary outcomes: all-cause death, nonfatal MI, nonfatal stroke, new-onset diabetes

Lifelines is a three-generation observational cohort and biobank designed to investigate universal risk factors and complex interactions between environmental, phenotypic and genomic factors in the development of chronic multifactorial diseases in a population-based sample of 167,729 subjects from the northern provinces of the Netherlands. Between 2006 and 2014 participants aged 6 months to 93 years had a baseline physical examination, and extensive questionnaires. Follow-up visits are scheduled every 5 years and in between participants receive follow-up questionnaires. Linkage is being established with medical registries and environmental data, the core of the project is dedicated data collection and biological sample storage, including genetic samples (“biobank”). GWAS have been done on >15,000 individuals. The design has statistical advantages, enables unique possibilities to study social characteristics, and offers practical benefits. Aim of LifeLines is to be a resource for the national and international scientific community.

The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Approximately 38 percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. The first examination took place over two years, from July 2000-July 2002. It was followed by three examination periods that were 17-20 months in length, and a fifth exam April 2010 – January 2012. Participants are contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality.

The characteristics of MIHYPHCTZ cohort (newly discovered participants with primary hypertension) allow to avoid structural changes associated with long lasting hypertension that can mask the characteristic genotype–phenotype relationship causing the initial development of hypertension and the response to drug. Moreover including only never-treated patients which allowed for avoidance of withdrawal effects (the rate of returning BP to pretreatment levels may vary between 1 month–1 year).
MIHYPHCTZ is a cohort of 220 European Americans newly discovered and never-treated participants with primary hypertension (defined by mean of three consecutive measurements of office SBP > 140 or DBP > 90 mmHg) enrolled after exclusion of secondary hypertension and a 1-month controlled diet (150 mmol sodium daily) run-in period. Patients were treated for 8 weeks with HCTZ, at a dose of 12.5 mg daily for 4 weeks and 25 mg daily for 4 further weeks. Before starting treatment, blood for chemistry, baseline plasma renin activity, aldosterone and urinary samples were collected.
A genome-wide association meta-analyses was conducted. Participants were from the Pharmacogenomic Evaluation of Antihypertensive Response study and the Genetic Epidemiology of Response to Antihypertensive study. The associated polymorphisms with blood pressure response that were found were replicated in independent samples of hydrochlorothiazide-treated European hypertensives. Two novel loci replicated for same-direction association of BP response: rs16960228 and rs2273359.

NORDIL was a prospective, randomized, open blinded-endpoint, multicenter, parallel-group clinical trial in hypertensive patients aged 50-74 years in Norway and Sweden. 4200 participants were randomized to a diltiazem-based treatment strategy or a conventional strategy including diuretics and/or beta blockers with a DBP goal of < 90 or a 10% reduction from baseline. They found diltiazem to be as effective as conventional therapy in preventing the combined primary end point of all stroke, MI, and other CV death.

PEAR was a multicenter prospective interventional trial that included 768 participants aged 17 to 65 years with uncomplicated hypertension. Both candidate gene and GWAS approaches will be used in order to identify genetic determinants of antihypertensive and adverse metabolic responses to thiazide diuretic, beta blocker, or their combination in self-identified Caucasians and African Americans. Participants were randomized to either HCTZ 25 mg or atenolol 100 mg , with 1 dose titration step followed by assessment at least 6 weeks later. Those with a BP >120/>70 continue to move through titration protocol. Home, office, and 24-hour ambulatory blood pressures as well as biologic samples (lipid, glucose, and uric acid) were collected. To date, 39 SNPs have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites.

PEAR2 was a randomized clinical trial where a GWAS study was conducted in 457 hypertensive self-identified Caucasian and African American individuals who received metoprolol 100 mg and chlorthalidone 25 mg in a sequential monotherapy design. Data collected include home and clinic blood pressure, blood samples for testing for adverse metabolic effects and other biomarkers (glucose, insulin, total cholesterol, LDL, HDL, TG, uric acid, potassium, sodium, creatinine, plasma renin activity), RNA, and DNA and urine sample. The data will be used for replication of findings from the PEAR trial, along with new discoveries in order to define genetic determinants of antihypertensive response and adverse metabolic responses.

In 2014 we looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in of never-treated mild-to-moderate essential hypertensive patients: 343 samples from Sardinia, Italy, were analyzed in combination with 142 never treated essential hypertensives with the same characteristics enrolled in Milan (Northern Italy). Treatment with hydrochlorothiazide 25mg/day started after an 8 week run in period under standardized dietary regimen and complete diagnostic workout to confirm the presence of the disease and to exclude secondary hypertension. BP response to hydrochlorothiazide was evaluated after 4 and 8 weeks of treatment. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry. Long term follow-up: ongoing. Cardiac (ECHO), renal, metabolic phenotypes available. Serum, plasma, and urine samples are available. The primary CV outcome was combined CV/cerebrovascular events while secondary outcomes were atrial fibrillation, CKD, new onset of diabetes.

This genome-wide association study aimed to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan in 372 never treated, mild-to-moderate essential hypertensives. The recruitment was made both in the Mainland of Italy and in Sardinia: all participants were genotyped (GWAS).
Participants received study drug losartan 50 mg/day after an 8 week run in period under standardized dietary regimen and complete diagnostic workout to confirm the presence of the disease and to exclude secondary hypertension. BP response to hydrochlorothiazide was evaluated after 4 and 8 weeks of treatment. Long term follow-up: ongoing. Cardiac (ECHO), renal, metabolic phenotypes available. Serum, plasma, and urine samples are available.
The primary CV outcome was combined CV/cerebrovascular events while secondary outcomes were atrial fibrillation, CKD, new onset of diabetes.
The findings were tested in two replication cohorts, GERA 2 and GENRES: the association of BP response to losartan with CAMK1D gene as a novel locus associated with blood pressure response to losartan was replicated in GENRES. Our findings may represent a useful tool to personalize the treatment of essential hypertension.

Secondary Prevention of Small Subcortical Strokes (SPS3) is a randomized, multicenter clinical trial (n = 3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomized, in a 2 × 2 factorial design, to antiplatelet therapy–325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind–and to one of two levels of systolic blood pressure targets–‘intensive’ (<130 mmHg) vs. ‘usual’ (130-149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischemic or hemorrhagic) is the primary outcome and will be analyzed separately for each intervention.
BP lowering: Mean SBP decreased for both BP lowering groups from baseline to the last follow-up, from 142.4 to 126.7mm Hg for the lower SBP target group and from 143.6 to 137.4mm Hg for the higher SBP target group. At baseline, participants in both groups used an average of 1.7±1.2 antihypertensive medications, which increased to a mean of 2.4±1.4 (lower group) and 1.8±1.4 (higher group) by the end-study visit. It took an average of 6 months for patients to reach their SBP target, sustained to the last follow-up. Black participants had the highest proportion of SBP ≥150mm Hg at both study entry (40%) and end-study visit (17%), as compared with whites (9%) and Hispanics (11%).
Antiplatelet therapy: After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64).

The TAICHI consortium is a well-phenotyped East Asian sample set consisting of >20,000 Han Chinese subjects drawn from seven principal cohorts. The consortium’s main aim is to identify genetic determinants of atherosclerosis and diabetes related traits in East Asians and to fine map validated loci identified in other race/ethnic groups. The main U.S academic sites participating in the Tai Chi consortium include Stanford University School of Medicine; Hudson-Alpha Biotechnology Institute and Los Angeles Biomedical Research Institute at Harbor-UCLA. The main academic sites in Taiwan include National Health Research Institute (NHRI); National Taiwan University Hospital (NTUH); Taipei and Taichung Veteran’s General Hospitals (VGH) and Tri-Service General Hospital (TSGH). Qualitative/categorical traits include coronary artery disease (CAD) either clinically or angiographically defined, type 2 diabetes mellitus (DM), and hypertension. Additional diabetes related microvascular complications include either retinopathy (DR) and/or nephropathy (DN). Cardiac specific quantitative traits other than those related to atherosclerosis include blood troponin levels, EKG derived intervals such as QT length, and cardiac imaging derived measures including LVH and pericardial fat.

This set of case-control studies conducted by the UCP team of researchers examined gene-drug interactions for cardiovascular drugs and the risk of myocardial infarction. Data were collected from the Dutch population-based registry of pharmacy records linked to hospital discharge records (PHARMO). Prior to collecting data from the PHARMO registry, they demonstrated feasibility of selecting patients from a coded database for a pharmacogenetic study and were able to approach them through community pharmacies, achieving reasonable response rates and without violating privacy rules. Using this registry, they found the Gly460Trp variant of the alpha-adducin gene, although previously associated with the salt-sensitive and diuretic responsive form of hypertension, does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics. A second case-control study in patients with hypercholesterolemia found that common genetic variability within the SLCO1B1 and ABCB1 genes is associated with the modification of the effectiveness of statins in the prevention of the clinical outcome, myocardial infarction. This was the first study to demonstrate this association.

Observational cohort, including 3818 whites. Data set consists of patients who:
1. received a prescription for an antihypertensive drug
2. had hypercholesterolemia (prescription for a cholesterol-lowering drug or total cholesterol >5.0 mmol/l)
having both conditions under 1 and 2
4. were diagnosed with (incident) diabetes type 2