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1.  Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes 
Background
Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.
Methods and Results
We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10−9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).
Conclusions
Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.
Clinical Trial Registration Information
clinicaltrials.gov; Identifiers: NCT00799396 and NCT00370045
doi:10.1161/CIRCGENETICS.111.964627
PMCID: PMC3715320  PMID: 23392654
pharmacogenomics; platelets; percutaneous coronary intervention; PEAR1; CYP2C19
2.  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
3.  Is Ticagrelor the Antiplatelet Therapy Panacea? 
doi:10.1161/CIRCGENETICS.110.958611
PMCID: PMC3052795  PMID: 21079054
clopidogrel; genetics; genotype; platelet function; ticagrelor; editorials
4.  Cost-Effectiveness of Cytochrome P450 2C19 Genotype Screening for Selection of Antiplatelet Therapy with Clopidogrel or Prasugrel 
Pharmacotherapy  2012;32(4):323-332.
Study Objective
To estimate the cost-effectiveness of genotype-guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype.
Design
Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.
Patients
Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention (PCI), consisting of three arms: those receiving genotype-guided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype.
Measurements and Main Results
All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 (CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio (ICER) for each event avoided in the genotype-guided therapy arm versus the other two arms. Genotype-guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel (ICER –$6760 [95% confidence interval (CI) –$6720 to –$6790]) or prasugrel (ICER –$11,710 [95% CI –$11,480 to –$11,950]) for all patients with-out regard to genotype. Genotype-guided therapy that included generic clopidogrel was dominant to prasugrel for all patients (ICER –$27,160 [95% CI –$27,890 to –$26,420]). Cost savings were not evident when genotype-guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients (ICER $2300 [95% CI $2290 to $2320]).
Conclusion
Genotype-guided antiplatelet therapy selection may be more cost-effective and may provide more clinical value due to fewer adverse outcomes.
doi:10.1002/PHAR.1048
PMCID: PMC3883873  PMID: 22461122
clopidogrel; prasugrel; cytochrome P450 2C19; pharmacogenomics; cost-effectiveness
5.  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
6.  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
7.  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
8.  Adrenergic-pathway Gene Variants Influence β-Blocker-related Outcomes after Acute Coronary Syndrome in a Race-specific Manner 
Objective
Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for US healthcare. Genetic polymorphisms in the adrenergic pathway appear to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor-blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown.
Background
BB after ACS is a measure of quality care, but the effectiveness across racial groups, is less clear.
Methods
A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African Americans) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors.
Results
The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion (D) carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (HR 0.46; CI 0.21, 0.99; p=0.047; race-by-genotype interaction p= 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (HR for RG vs. GG =2.10; CI 1.14, 3.86; RR vs. GG =2.65; CI 1.38, 5.08; p=0.013; race-by-genotype interaction p=0.096).
Conclusions
Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasian and African Americans may illuminate opportunities to improve BB therapy in these groups.
doi:10.1016/j.jacc.2012.02.051
PMCID: PMC3678950  PMID: 22703928
9.  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
10.  Blood Pressure Responses and Metabolic Effects of Hydrochlorothiazide and Atenolol 
American Journal of Hypertension  2011;25(3):359-365.
BACKGROUND
Thiazides and β-blockers cause adverse metabolic effects (AMEs), but whether these effects share predictors with blood pressure (BP) response is unknown. We aimed to determine whether AMEs are correlated with BP response in uncomplicated hypertensives.
METHODS
In a multicenter, open-label, parallel-group trial, we enrolled 569 persons, aged 17–65, with random assignment to 9 weeks of daily hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by 9 weeks of add-on therapy with the alternate agent. Measurements included home BP, averaged over 1 week, weight and fasting levels of serum glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and uric acid (UA) before and after monotherapy and after add-on therapy.
RESULTS
Increases in UA correlated with reductions in systolic BP (SBP) (r = −0.18; P = 0.003) and diastolic BP (DBP) (r = −0.20; P = 0.001) following HCTZ monotherapy and add-on therapy (r = −0.27 and r = −0.21, respectively; both P < 0.001). After adjustment for age, race, gender, and baseline body mass index (BMI), only the correlation between UA and DBP response became nonsignificant. Reductions in HDL correlated with systolic response following atenolol monotherapy (r = 0.18; P = 0.002) and with systolic and diastolic response following add-on therapy (r = 0.30 and r = 0.24, respectively; both P < 0.0001). These correlations remained significant after covariate adjustment. BP responses were not correlated with changes in glucose, LDL, triglycerides, or weight following either therapy.
CONCLUSIONS
BP response correlated with changes in UA following HCTZ therapy and HDL following atenolol therapy. No other significant correlations were observed between BP response and AMEs, suggesting that these effects generally do not share predictors. Patients should be monitored for AMEs, regardless of BP response.
doi:10.1038/ajh.2011.215
PMCID: PMC3288583  PMID: 22089105
thiazide diuretics; atenolol; β-blockers; blood pressure; hydrochlorothiazide; hypertension; metabolic effects
11.  Evolving research and stakeholder perspectives on pharmacogenomics 
doi:10.1001/jama.2011.1343
PMCID: PMC3559013  PMID: 21934059
pharmacogenomics; stakeholders; healthcare system
12.  CXCL5 polymorphisms are associated with variable blood pressure in cardiovascular disease-free adults 
Human Genomics  2012;6(1):9.
Objective
Leukocyte count has been associated with blood pressure, hypertension, and hypertensive complications. We hypothesized that polymorphisms in the CXCL5 gene, which encodes the neutrophilic chemokine ENA-78, are associated with blood pressure in cardiovascular disease (CVD)-free adults and that these polymorphisms are functional.
Methods and results
A total of 192 community-dwelling participants without CVD or risk equivalents were enrolled. Two CXCL5 polymorphisms (−156 G > C (rs352046) and 398 G > A (rs425535)) were tested for associations with blood pressure. Allele-specific mRNA expression in leukocytes was also measured to determine whether heterozygosity was associated with allelic expression imbalance. In −156 C variant carriers, systolic blood pressure (SBP) was 7 mmHg higher than in −156 G/G wild-type homozygotes (131 ± 17 vs. 124 ± 14 mmHg; P = 0.008). Similarly, diastolic blood pressure (DBP) was 4 mmHg higher in −156 C variant carriers (78 ± 11 vs. 74 ± 11 mmHg; P = 0.013). In multivariate analysis of SBP, age, sex, body mass index, and the −156 G > C polymorphism were identified as significant variables. Age, sex, and the −156 G > C SNP were further associated with DBP, along with white blood cells. Allelic expression imbalance and significantly higher circulating ENA-78 concentrations were noted for variant carriers.
Conclusion
CXCL5 gene polymorphisms are functional and associated with variable blood pressure in CVD-free individuals. The role of CXCL5 as a hypertension- and CVD-susceptibility gene should be further explored.
doi:10.1186/1479-7364-6-9
PMCID: PMC3505480  PMID: 23245743
CXCL5; ENA-78; Blood pressure; Hypertension; Leukocytes
13.  Chromosome 9p21 Haplotypes and Prognosis in Caucasian and African American Patients with Coronary Artery Disease 
Background
While numerous SNPs in Chromosome 9p21 have been associated with coronary artery disease (CAD) and incident MI in Caucasians, there are limited and conflicting reports on the association of this locus with prognosis in Caucasians 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 hypertensive CAD patients of multiple races/ethnicities in INVEST GENES (the INternational VErapamil SR Trandolapril STudy GENetic Substudy, n= 1,460, n = 5,979 for 2 SNPs) and with replication testing of 4 SNPs in the INFORM (INvestigation oF Outcomes from acute coronary syndRoMe; n=714) study of acute coronary syndrome (ACS) patients. In INVEST, the haplotype comprised of the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in Caucasians (OR, 95% CI: 0.72, 0.57–0.92, p = 0.0085) but not blacks (1.21, 0.68–1.24, p = 0.52) or Hispanics (0.96, 0.65–1.44, p=0.86). A less commonly reported LD block was associated with worse prognosis in INVEST among both Caucasians (OR=1.52 (1.20–1.93), p = 0.0006) and African Americans (OR = 4.11 (1.55–10.88), p = 0.004).
Conclusions
Our findings suggest 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 LD block warrants further investigation.
doi:10.1161/CIRCGENETICS.110.959296
PMCID: PMC3101633  PMID: 21372283
chromosome 9p21; cardiovascular outcomes; genetic polymorphisms; INVEST; INFORM
14.  Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response 
Background
To determine whether office, home, ambulatory daytime and nighttime blood pressure (BP) responses to antihypertensive drug therapy measure the same signal and which method provides greatest power to identify genetic predictors of BP response.
Methods
We analyzed office, home, ambulatory daytime and nighttime BP responses in hypertensive adults randomized to atenolol (N = 242) or hydrochlorothiazide (N = 257) in the Pharmacogenomic Evaluation of Antihypertensive Responses Study. Since different measured BP responses may have different predictors, we tested the "same signal" model by using linear regression methods to determine whether known predictors of BP response depend on the method of BP measurement. We estimated signal-to-noise ratios and compared power to identify a genetic polymorphism predicting BP response measured by each method separately and by weighted averages of multiple methods.
Results
After adjustment for pretreatment BP level, known predictors of BP response including plasma renin activity, race, and sex were independent of the method of BP measurement. Signal-to-noise ratios were more than 2-fold greater for home and ambulatory daytime BP responses than for office and ambulatory nighttime BP responses and up to 11-fold greater for weighted averages of all four methods. Power to identify a genetic polymorphism predicting BP response was directly related to the signal-to-noise ratio and, therefore, greatest with the weighted averages.
Conclusion
Since different methods of measuring BP response to antihypertensive drug therapy measure the same signal, weighted averages of the BP responses measured by multiple methods minimize measurement error and optimize power to identify genetic predictors of BP response.
doi:10.1186/1479-5876-10-47
PMCID: PMC3342146  PMID: 22413836
hypertension; blood pressure monitoring; antihypertensive drug therapy; beta-blocker; thiazide diuretic; plasma renin activity
15.  Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive treated patients 
Pharmacogenetics and genomics  2011;21(1):42-49.
Objectives
The G-protein coupled receptor kinases GRK2 and GRK5 are important regulators of beta-adrenergic signaling. This study characterized single nucleotide polymorphisms 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 Gln41Leuwas tested in 418patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leuon death, myocardial infarction or stroke in treated hypertensive patients was evaluated in a case-control cohort (1:3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy (INVEST GENES) 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 (rs1894111G>A) showed a signal for association with systolic and diastolic BP(SBP, DBP) response to hydrochlorothiazide in whites(DBP: −11.29±3.74 mmHg (G/A) vs. −4.26±4.79 mmHg (G/G), P = 0.0034 and SBP: −18.37±14.90 mmHg (G/A), −8.11±7.55 mmHg (G/G), P = 0.0191).
Conclusions
The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.
doi:10.1097/FPC.0b013e328341e911
PMCID: PMC3028503  PMID: 21127457
GRK5; GRK2; ADRBK1; polymorphism; hypertension; beta-blocker; atenolol; diuretic; hydrochlorothiazide
16.  Genetic Variation in the Beta 2 Subunit of the Voltage-Gated Calcium Channel (CACNB2) and Pharmacogenetic Association with Adverse Cardiovascular Outcomes in the International Verapamil SR-Trandolapril Study-Genetic Substudy (INVEST-GENES) 
Background
Polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.
Methods and Results
SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292 and rs61839258) and a GWAS identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5,598 hypertensive patients with coronary artery disease randomized to a beta-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in INVEST-GENES. Reporter gene assays were conducted on the promoter SNP showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (p for interaction = 0.002). In Caucasians, rs2357928 GG patients randomized to CCB were more likely to experience adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (CCB vs. BB) of 2.35 (1.19-4.66), p = 0.014. There was no evidence for such treatment difference in AG (1.16, 0.75-1.79, p = 0.69) and AA individuals (0.63, 0.36-1.11, p = 0.11). This finding was consistent in Hispanics and African Americans. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in Caucasians or African Americans. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.
Conclusions
These data suggest genetic variation within CACNB2 may influence treatment related outcomes in high risk hypertensive patients.
Clinical Trial Registration Information
Clinical trial identifier: NCT00133692, URL: http://clinicaltrials.gov/ct/gui/show/NCT00133692).
doi:10.1161/CIRCGENETICS.110.957654
PMCID: PMC3060561  PMID: 21156931
Genetic variations; CACNB2; hypertension; cardiovascular outcomes; INVEST-GENES
17.  Interaction between the UCP2 −866 G > A polymorphism, diabetes, and β-blocker use among patients with acute coronary syndromes 
Pharmacogenetics and genomics  2010;20(4):231-238.
Objective
UCP2 −866G > A (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for β-blocker response, particularly among patients with diabetes. We assessed the function of −866G > A and its role as a modifier of β-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort.
Methods
ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n = 468) were assessed. The influence of −866G > A on β-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of −866G > A, we compared uncoupling protein 2 (UCP2) expression in the skeletal muscle of obese participants by genotype and compared the activity of UCP2 luciferase promoters with −866G and −866A alleles.
Results
An interaction between −866G > A and β-blocker treatment was found in individuals with diabetes (P = 0.002) but not those without (P = 0.79). Among G/G individuals with diabetes, discharge β-blocker use was associated with an 80% reduction in cardiac rehospitalization (adjusted hazard ratio: 0.20; 95% confidence interval: 0.04–1.02). In contrast, among A-carrier patients with diabetes, there was an 11-fold increase in cardiac rehospitalizations with discharge β-blocker therapy (adjusted hazard ratio: 11.75; 95% confidence interval: 1.28-108.2). Promoter activity assays showed that −866G had greater cyclic AMP response element binding protein-responsiveness compared with −866A, and compared with −866A carriers G/G individuals exhibited increased UCP2 expression in the skeletal muscle.
Conclusion
We identified a significant interaction between −866G > A and β-blocker response among ACS patients with diabetes. Furthermore, −866G conferred greater gene transcriptional activity than −866A in cell lines and in obese patients. These findings may help us gain insight into the mechanisms underlying the beneficial and detrimental effects of β-blockers in those with diabetes.
doi:10.1097/FPC.0b013e3283377abc
PMCID: PMC2842450  PMID: 20145583
acute coronary syndromes; gene-environment interaction; pharmacogenetics; type 2 diabetes
18.  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
19.  Aromatase Gene Polymorphisms Are Associated with Survival among Patients with Cardiovascular Disease in a Sex-Specific Manner 
PLoS ONE  2010;5(12):e15180.
Introduction
CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.
Methods
Caucasian individuals from two independent populations were assessed: 1) a prospective cohort of patients with acute coronary syndromes with 3-year mortality follow-up (n = 568) and 2) a nested case-control study from a randomized, controlled trial of hypertension patients with stable coronary disease in which the primary outcome was death, nonfatal myocardial infarction (MI) or nonfatal stroke (n = 619). Six CYP19A1 SNPs were genotyped (-81371 C>T, -45965 G>C, M201T, R264C, 80 A>G, and +32226 G>A). The sex*genotype interaction term was assessed for the primary outcome and compared by genotype in men and women when a significant interaction term was identified.
Results
We identified a significant interaction between -81371 C>T and sex (p = 0.025) in the ACS population. The variant allele was associated with a 78% increase in mortality in men (HR 1.78, 95% confidence interval [CI] 1.08-2.94) and a nonsignificant 42% decrease in mortality among women (HR 0.58, 95% CI 0.22-1.54). We identified a similar association in the hypertensive CAD group, the -81371 C>T*sex interaction term was p<0.0001, with an associated 65% increase in death, MI, or stroke (HR 1.65, 95% CI 1.00-2.73) in men and a 69% decrease (HR 0.31, 95% CI 0.16-0.6) in women.
Conclusions
Using two independent populations, this study is the first to document a significant interaction between CYP19A1 genotype and sex on cardiovascular outcomes. These findings could illuminate potential mechanisms of sex differences in cardiovascular disease outcomes.
doi:10.1371/journal.pone.0015180
PMCID: PMC3000815  PMID: 21170323
20.  Plasma Renin Activity Predicts Blood Pressure Responses to β-Blocker and Thiazide Diuretic as Monotherapy and Add-On Therapy for Hypertension 
American journal of hypertension  2010;23(9):1014-1022.
BACKGROUND
Age and race categories or renin profiling have been recommended to predict blood pressure responses to monotherapy with a β-blocker or thiazide diuretic. Whether these or other characteristics predict blood pressure responses when the drugs are administered as add-on therapy is uncertain.
METHODS
We evaluated predictors of blood pressure response in 363 men and women ≤65 years of age with primary hypertension (152 blacks, 211 whites), 86 of whom (24%) were untreated and 277 of whom (76%) were withdrawn from previous antihypertensive drugs before randomization to either atenolol followed by addition of hydrochlorothiazide (N = 180) or hydrochlorothiazide followed by addition of atenolol (N = 183). Responses were determined by home blood pressure averages before and after each drug administration. Race, age, plasma renin activity, and other characteristics including pretreatment blood pressure levels were incorporated into linear regression models to quantify their contributions to prediction of blood pressure responses.
RESULTS
Plasma renin activity and pretreatment blood pressure level consistently contributed to prediction of systolic and diastolic responses to each drug administered as mono- and as add-on therapy. Higher plasma renin activity was consistently associated with greater blood pressure responses to atenolol and lesser responses to hydrochlorothiazide. The predictive effects of plasma renin activity were statistically independent of race, age, and other characteristics.
CONCLUSIONS
Plasma renin activity and pretreatment blood pressure level predict blood pressure responses to atenolol and hydrochlorothiazide administered as mono- and as add-on therapy in men and women ≤65 years of age.
doi:10.1038/ajh.2010.98
PMCID: PMC2941699  PMID: 20725057
antihypertensive drug therapy; blood pressure; hypertension; plasma renin activity; thiazide diuretic; β-blocker
21.  A PPARα Promoter Variant Impairs ERR-Dependent Transactivation and Decreases Mortality after Acute Coronary Ischemia in Patients with Diabetes 
PLoS ONE  2010;5(9):e12584.
Activation of peroxisome proliferator-activated receptor alpha (PPARα) occurs in animal models of diabetes (DM) and is implicated in pathological responses to myocardial ischemia. Using bioinformatics, we identified a single nucleotide polymorphism (SNP) in the PPARα gene promoter (PPARA −54,642 G>A; rs135561) that altered the consensus sequence for a nuclear receptor binding site. Electrophoretic mobility shift assays showed that the domain bound two known PPARA transcriptional activators, estrogen-related receptor (ERR)-α and -γ and that PPARA G bound with greater affinity than PPARA A (>2-fold; P<0.05). Likewise, promoter-reporter analyses showed enhanced transcriptional activity for PPARA G vs. PPARA A for both ERR-α and -γ (3.1 vs.1.9-fold; P<0.05). Since PPARα activation impairs post-ischemic cardiac function in experimental models of DM, we tested whether decreased PPARA transcription in PPARA A carriers favorably impacted outcome after acute coronary ischemia in 705 patients hospitalized with acute coronary syndromes (ACS; 552 Caucasian, 106 African American). PPARA A allele frequencies were similar to non-diseased subjects. However, PPARA genotype correlated with 5-year mortality in diabetic (22.2% AA vs. 18.8% AG vs. 39.5% GG; P = 0.008), but not non-diabetic (P = 0.96) subjects (genotype by diabetes interaction P = 0.008). In the diabetic ACS subjects, PPARA A carriers had strikingly reduced all-cause mortality compared to PPARA G homozygotes, (unadjusted HR 0.44, 95% CI 0.26–0.75; P = 0.003; adjusted HR 0.48, 95% CI 0.27–0.83; P = 0.009). Consistent with previous descriptions of PPARα in experimental models and human disease, we describe a novel PPARA promoter SNP that decreases transcriptional activation of PPARA and protects against mortality in diabetic patients after ACS.
doi:10.1371/journal.pone.0012584
PMCID: PMC2933242  PMID: 20838448
22.  CACNA1C gene polymorphisms, cardiovascular disease outcomes and treatment response 
Background
The gene encoding the target of calcium channel blockers, the α1c-subunit of the L-type calcium channel (CACNA1C) has not been well characterized and only small pharmacogenetic studies testing this gene have been published to date.
Methods and Results
Resequencing of CACNA1C was performed followed by a nested case-control study of the INternational VErapamil SR/trandolapril STudy (INVEST) GENEtic Substudy (INVEST-GENES). Of 46 polymorphisms identified, eight were assessed in the INVEST-GENES. Rs1051375 was found to have a significant interaction with treatment strategy (p=0.0001). Rs1051375 A/A genotype was associated with a 46% reduction in the primary outcome among those randomized to verapamil SR treatment compared to atenolol treatment (OR 0.54 95% CI 0.32-0.92). In heterozygous A/G individuals, there was no difference in the occurrence of the primary outcome when randomized to verapamil SR versus atenolol treatment (OR 1.47 95% CI 0.86-2.53), while homozygous G/G individuals had a greater than 4-fold increased risk of the primary outcome with verapamil treatment compared to those randomized to atenolol treatment (OR 4.59 95% CI 1.67-12.67). We did not identify allelic expression imbalance or differences in mRNA expression in heart tissue by rs1051375 genotype.
Conclusions
Variation in CACNA1C is associated with treatment response among hypertensive patients with stable coronary artery disease. Our data suggest a genetically-defined group of patients that benefit most from calcium channel blocker therapy, a group that benefits most from β-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent.
doi:10.1161/CIRCGENETICS.109.857839
PMCID: PMC2761685  PMID: 20031608
genetics; pharmacology; ion channels; calcium; pharmacogenetics
23.  Comparison of Office, Ambulatory, and Home Blood Pressure Antihypertensive Response to Atenolol and Hydrochlorthiazide 
Office, home, and ambulatory blood pressure (BP) demonstrate variable associations with outcomes. The authors sought to compare office BP (OBP), home BP (HBP), and ambulatory BP (ABP) for measuring responses to hydrochlorothiazide (HCTZ), atenolol, and their combination. After completing washout, eligible patients were randomized to atenolol 50 mg or HCTZ 12.5 mg daily. Doses were doubled after 3 weeks and the alternate drug was added after 6 weeks if BP was >120/70 mm Hg (chosen to allow maximum opportunity to assess genetic associations with dual BP therapy in the parent study). OBP (in triplicate), HBP (twice daily for 5 days), and 24-hour ABP were measured at baseline, after monotherapy, and after combination therapy. BP responses were compared between OBP, HBP, and ABP for each monotherapy and combination therapy. In 418 patients, OBP overestimated BP response compared with HBP, with an average 4.6 mm Hg greater reduction in systolic BP (P<.0001) and 2.1 mm Hg greater reduction in diastolic BP (P<.0001) across all therapies. Results were similar for atenolol and HCTZ monotherapy. ABP response was more highly correlated with HBP response (r=0.58) than with OBP response (r=0.47; P=.04). In the context of a randomized clinical trial, the authors have identified significant differences in HBP, OBP, and ABP methods of measuring BP response to atenolol and HCTZ monotherapy.
doi:10.1111/j.1751-7176.2009.00185.x
PMCID: PMC2841560  PMID: 20047624
24.  Serum Monocyte Chemoattractant Protein-1 Concentrations Associate With Diabetes Status but Not Arterial Stiffness in Children With Type 1 Diabetes 
Diabetes Care  2008;32(3):465-467.
OBJECTIVE
The relationship between circulating markers of inflammation and arterial stiffness in children with type 1 diabetes is not well studied. We tested whether inflammatory monocyte chemoattractant protein (MCP)-1 concentrations correlate with arterial stiffness or type 1 diabetes status.
RESEARCH DESIGN AND METHODS
MCP-1 concentrations and radial tonometry data were available for 98 children with type 1 diabetes and 55 healthy control subjects. Arterial stiffness was calculated as augmentation index corrected for a heart rate of 75 (AI75). Correlation between MCP-1 and AI75 and differences in MCP-1 concentrations between case and control subjects were tested.
RESULTS
MCP-1 was significantly higher in children with type 1 diabetes than in control subjects (P < 0.001). However, there were no correlations between MCP-1 and AI75 in the overall sample or upon stratification by type 1 diabetes status (range P = 0.28–0.66).
CONCLUSIONS
Circulating MCP-1 was not associated with arterial stiffness but was significantly elevated in children with type 1 diabetes, indicating a proinflammatory state in children as young as 10 years. The clinical significance of MCP-1 elevation in type 1 diabetes needs further investigation.
doi:10.2337/dc08-1849
PMCID: PMC2965824  PMID: 19092169
25.  α-ADDUCIN POLYMORPHISM ASSOCIATED WITH INCREASED RISK OF ADVERSE CARDIOVASCULAR OUTCOMES: RESULTS FROM INVEST-GENES 
American heart journal  2008;156(2):397-404.
Background
The α-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 between the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 hypertensive coronary artery disease patients, who participated in the INternational VErapamil SR-trandolapril STudy (INVEST) and provided genomic DNA. The primary outcome was defined as 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 (HR) 2.62; 95% confidence interval (CI) 1.23–5.58; p = .012), with a similar trend in Whites and Hispanics, albeit a smaller magnitude of effect (adjusted HR 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 ADD1 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.
doi:10.1016/j.ahj.2008.03.007
PMCID: PMC2547143  PMID: 18657677
pharmacogenetics; ADD1; diuretics; cardiovascular outcomes

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