Nighttime administration of high-dose, sustained-release melatonin does not decrease nocturnal blood pressure in African-American patients: Results from a preliminary randomized, crossover trial.

OBJECTIVES: This preliminary study tested whether a high-dose, sustained-release form of melatonin reduced 24-hour blood pressure in African-Americans. DESIGN: Randomized, placebo-controlled, crossover pilot study of 40 self-defined African-American patients with essential hypertension. SETTINGS/LOCATION: Urban, academic medical center and associated outpatient clinics. INTERVENTIONS: Patients ingested either melatonin (high dose [24 mg], sustained-release formulation] or placebo in randomized order over a 4-week period. OUTCOME MEASURES: Mean nighttime and daytime systolic and diastolic blood pressures, as measured with 24-hour ambulatory blood pressure monitors. The primary outcome was mean nighttime systolic blood pressure. RESULTS: There were no statistically differences between melatonin and placebo conditions in mean nighttime or daytime systolic or diastolic blood pressures. CONCLUSIONS: In contrast with studies in other populations, this preliminary study showed that nighttime dosing of continuous-release melatonin had no significant effect on nocturnal blood pressure in African Americans with essential hypertension when compared to placebo.

Melatonin Pathway and Atenolol-Related Glucose Dysregulation: Is There a Correlation?

Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.

Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide.

Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.

OBJECTIVE: Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia. METHODS: A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis. RESULTS: Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL(-1) were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the 'top' SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79 × 10(-7) ) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs. CONCLUSION: Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate.

Metoprolol is a selective ß-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty-one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response-guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P < 0.0001), with poor and intermediate metabolizers showing greater reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not determinants of variability in metoprolol response or tolerability.

Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.

Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.

Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression.

A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide (HCTZ) in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and HCTZ response in an independent sample of 746 Caucasians and African-Americans randomized to HCTZ or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4 mmHg, P=0.0275; diastolic: 2.5 mmHg, P=0.0196) responses to HCTZ vs T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as HCTZ specific. Expression analyses in HCTZ-treated African-Americans showed differential pre-treatment leukocyte YEATS4 expression between rs7297610 genotype groups (P=0.024), and reduced post-treatment 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.

Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment.

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.

Hydrochlorothiazide and atenolol combination antihypertensive therapy: effects of drug initiation order.

For combination antihypertensive therapy with thiazide diuretics and beta-blockers, the effect of the order of initiation of the drugs on the outcome has not been tested. Patients with uncomplicated hypertension were randomized to receive either hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by addition of the alternative drug. Blood pressure (BP) responses were evaluated by race and order of drug initiation. A total of 368 participants received combination therapy. Among the participants, blacks showed a greater BP-lowering effect than whites did with HCTZ monotherapy (-13.0/-7.4 mm Hg vs. -8.0/-4.2 mm Hg, P < 0.001) but a smaller BP-lowering effect than did whites with atenolol monotherapy (-1.1/-2.9 mm Hg vs. -9.9/-9.2 mm Hg, P < 0.0001). These differences were not evident during combination therapy. However, both groups showed greater response to HCTZ + atenolol than to atenolol + HCTZ (-19.1/-14.2 mm Hg vs. -15.6/-11.3 mm Hg, P < 0.0001). Despite optimal dosing of HCTZ + atenolol, only two-thirds of the participants achieved BP control. In HCTZ/atenolol combination antihypertensive therapy, the order in which the drugs are initiated affects total BP lowering during the first 4-6 months of therapy.

Determinants of renal volume in autosomal-dominant polycystic kidney disease.

The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker.

Multilocus effects of the renin-angiotensin-aldosterone system genes on blood pressure response to a thiazide diuretic.

BACKGROUND: The renin-angiotensin-aldosterone (RAA) system regulates blood pressure (BP) levels and influences responses to antihypertensive medications. Variation in RAA system genes has been reported to influence interindividual differences in BP levels and the occurrence of hypertension (HTN). METHODS: We evaluated the relationship between variation in genes of the RAA system and interindividual differences in BP response to a thiazide diuretic. Analyses were carried out in a race- and gender-specific manner in 255 unrelated hypertensive African-Americans (125 men and 130 women) and 246 unrelated hypertensive non-Hispanic Whites (133 men and 113 women). RESULTS: The angiotensin II receptor (AT(1)R) A1166C and angiotensinogen G-6A polymorphisms had a significant effect on systolic BP response to the diuretic in African-American women. Multilocus analyses indicated that the effects of these genes combined additively to influence response. Results of a permutation test to adjust for multiple comparisons and the possible nonindependence among genotypes remained significant at the P=0.003 level. CONCLUSIONS: Among African-American women, particular gene variations in the RAA system have additive effects on BP response to a thiazide diuretic.

Use of gene markers to guide antihypertensive therapy.

Sequencing of the human genome has elevated the potential for genetic information to aid in the prevention, diagnosis, and treatment of common chronic diseases. One beneficial application of genetic information is the identification of variants that influence response to pharmaceutical agents used to lower blood pressure and prevent target organ complications of hypertension. Knowledge of genetic variants that influence blood pressure response to antihypertensive drugs may allow more individualized tailoring of antihypertensive drug therapy, and provide greater insight into the molecular mechanisms regulating blood pressure levels and causing hypertension.

Validity of the aldosterone-renin ratio used to screen for primary aldosteronism.

OBJECTIVE: To determine whether the calculated ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA), a proposed screening test for primary aldosteronism, provides a renin-independent measure of circulating aldosterone that is suitable to judge whether PAC is inappropriately elevated relative to PRA. SUBJECTS AND METHODS: This study consisting of 221 black and 276 white subjects with previously diagnosed essential hypertension was conducted between 1996 and 2000. Antihypertensive drugs were withdrawn for at least 4 weeks; PAC and PRA were measured while subjects were supine and then seated after 30 minutes of ambulation. The seated measurements were repeated after 4 weeks of oral diuretic therapy with hydrochlorothiazide (25 mg/d). RESULTS: The variation in the aldosterone-renin ratio was strongly and inversely dependent on PRA (R2=0.71; P<.001). When subjects changed position from supine to seated, the increase in mean +/- SD PRA (from 1.18 +/- 1.06 to 1.31 +/- 1.19 ng x mL(-1) x h(-1); P<.001) was associated with an increase in the mean ratio (from 18.6 +/- 52.8 to 25.8 +/- 38.1 h x 10(2); P<.001), whereas the increase in mean +/- SD PRA in response to diuretic therapy (from 1.31 +/- 1.19 to 2.72 +/- 2.67 ng x mL(-1) x h(-1); P=.007) was associated with a decrease in the mean ratio (from 25.8 +/- 38.1 to 16.4 +/- 31.6 h 10(2); P<.001). CONCLUSION: In patients with previously diagnosed essential hypertension, calculation of the aldosterone-renin ratio does not provide a renin-independent measure of circulating aldosterone that is suitable for determining whether PAC is elevated relative to PRA. Because elevation of the aldosterone-renin ratio is predominantly an indicator of low PRA, its perceived value in screening for primary aldosteronism most likely derives from additional diagnostic tests being done in patients with low-renin hypertension.

Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease.

Hypertension, which occurs commonly and early in autosomal dominant polycystic kidney disease (ADPKD), affects both renal and patient outcome. However, there is no consensus about the type of antihypertensive therapy that is most appropriate for patients with ADPKD. This historical prospective, nonrandomized study was designed to investigate the effect on renal function of diuretics versus angiotensin-converting enzyme (ACE) inhibitors in hypertensive patients with ADPKD who entered the study with comparable renal function. Among hypertensive ADPKD patients followed in our center, patients taking diuretics without any ACE inhibitors were included in the diuretic group (n = 14, male/female ratio 5/9, mean age 47 years), whereas patients taking ACE inhibitors but no diuretics were included in the ACE inhibitor (ACEI) group (n = 19, male/female ratio 11/8, mean age 41 years). For comparable blood pressure control, 21% of the ACEI group and 64% of the diuretic group (p < 0.05) needed additional antihypertensive medications. After an average follow-up period of 5.2 years, the creatinine clearance decreased significantly in the diuretic group (74 vs. 46 ml/min/1.73 m2, p < 0.0001) and in the ACEI group (83 vs. 71 ml/min/1.73 m2, p = 0.0005). The decrement in creatinine clearance was significantly larger in the diuretic group than the ACEI group (p < 0.05). The annual decrease in creatinine clearance was 5.3 ml/min/1.73 m2 in the diuretic group and 2.7 ml/min/1.73 m2 in the ACEI group (p < 0.05). A significant increase in urinary protein excretion occurred in the diuretic but not in the ACEI group. Hypertensive ADPKD patients treated with diuretics had a faster loss of renal function as compared with patients treated with ACE inhibitors, despite similar blood pressure control. This result will need to be further examined in a randomized study.

C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic.

The T allele of the C825T polymorphism of the gene encoding the beta(3)-subunit of G proteins has been associated with increased sodium-hydrogen exchange and low renin in patients with essential hypertension. To assess its association with blood pressure response to diuretic therapy, we measured the C825T polymorphism in 197 blacks (134 men, 63 women) and 190 non-Hispanic whites (76 men, 114 women) with essential hypertension (mean+/-SD age 48+/-7 years), who underwent monotherapy with hydrochlorothiazide for 4 weeks. Mean declines in systolic and diastolic blood pressures were 6+/-2 (P:<0.001) and 5+/-1 (P:<0.001) mm Hg greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between the homozygous groups. Other univariate predictors of greater blood pressure responses included black race, female gender, higher pretreatment blood pressure, older age, lower waist-to-hip ratio, and measures of lower renin-angiotensin-aldosterone system activity. After the effects of the other predictors were considered, the TT genotype remained a significant predictor of greater declines in systolic and diastolic blood pressures. Thus, the C825T polymorphism of the G protein beta(3)-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy.

Antihypertensive pharmacogenetics: getting the right drug into the right patient.

Pharmacogenetic investigation seeks to identify genetic factors that contribute to interpatient and interdrug variation in responses to antihypertensive drug therapy. Classical studies have characterized single gene polymorphisms of drug metabolizing enzymes that are responsible for large interindividual differences in pharmacokinetic responses to several antihypertensive drugs. Progress is being made using candidate gene and genome scanning approaches to identify and characterize many additional genes influencing pharmacodynamic mechanisms that contribute to interindividual differences in responses to antihypertensive drug therapy. Knowledge of polymorphic variation in these genes will help to predict individual patients' blood pressure responses to antihypertensive drug therapy and may also provide new insights into molecular mechanisms responsible for elevation of blood pressure.

Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease.

Hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) have a faster progression to end-stage renal disease (ESRD) than their normotensive counterparts. The aim of this prospective, randomized study is to compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor enalapril as first-line therapy on blood pressure, renal function, and urinary albumin excretion in hypertensive patients with ADPKD. Twenty-four patients with ADPKD with hypertension with creatinine clearances (Ccrs) greater than 50 mL/min/1.73 m(2) were included in the study. Twelve patients received amlodipine (mean dose, 9 mg/d), and 12 patients received enalapril (mean dose, 17 mg/d). The patients were followed up for 5 years. Baseline mean arterial pressures, which were 109 +/- 3 mm Hg in the amlodipine group and 108 +/- 3 mm Hg in the enalapril group, decreased significantly after 1 year of follow-up (amlodipine, 96 +/- 3 mm Hg; P < 0.005; enalapril, 89 +/- 2 mm Hg; P < 0.0005) and remained stable at year 5 (amlodipine, 97 +/- 3 mm Hg; P < 0.0005 versus baseline; enalapril, 94 +/- 3 mm Hg; P < 0.005 versus baseline). Ccrs, which were 83 +/- 5 mL/min/1.73 m(2) in the amlodipine group and 77 +/- 6 mL/min/1.73 m(2) in the enalapril group, remained stable after 1 year of follow-up and decreased significantly at year 3 in both groups (amlodipine, 67 +/- 5 mL/min/1.73 m(2); P < 0.01 versus year 1 and baseline; enalapril, 58 +/- 4 mL/min/1.73 m(2); P < 0.05 versus year 1 and P < 0.0005 versus baseline) with no significant change thereafter. No change was observed in urinary albumin-creatinine ratio in the amlodipine group (baseline, 68 +/- 21 mg/g; year 1, 52 +/- 21 mg/g; year 5, 148 +/- 74 mg/g), whereas it decreased significantly in the enalapril group at year 1 (baseline, 23 +/- 4 mg/g; year 1, 13 +/- 3 mg/g; P < 0.05) and remained stable until the end of the study at year 5 (14 +/- 6 mg/g). The investigators concluded that blood pressure was similar in both groups but only enalapril had a significant effect to sustain decreased urinary albumin excretion for a 5-year follow-up. Although proteinuria has been considered a surrogate of renal disease progression, further studies will be necessary to confirm this hypothesis in ADPKD, because after 5 years, no differences in renal function were observed between the enalapril and amlodipine groups. In comparison with patients with ADPKD with uncontrolled hypertension, effective control of blood pressure, as undertaken in the present study, should delay the onset of ESRD by approximately 15 years.

Reversal of left ventricular hypertrophy with angiotensin converting enzyme inhibition in hypertensive patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension occurs commonly and early in the natural history of autosomal dominant polycystic kidney disease (ADPKD), affecting both renal and patient outcome. Activation of the renin angiotensin aldosterone system due to cyst expansion and local renal ischaemia plays an important role in the development of ADPKD related hypertension and left ventricular hypertrophy (LVH), a known important risk factor for cardiovascular morbidity and mortality. The aim of this study was to investigate the effects of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on renal function, blood pressure and LVH in hypertensive ADPKD patients. METHODS: Fourteen hypertensive ADPKD patients (11 men, 3 women; mean age: 40 years) were included in the study. All patients had LVH and creatinine clearance (Cer) greater than 50 ml/min/1.73 m2. The patients were followed for 7 years on enalapril therapy. The effects of enalapril on renal function, blood pressure and LVH were investigated. RESULTS: Baseline measurements of mean arterial pressure (MAP), Ccr and left ventricular mass index (LVMI) were 110 +/- 2 mmHg, 84 +/- 6 ml/min/1.73 m2 and 146 +/- 4 g/m2, respectively. After one year of enalapril therapy there was a significant decrease in MAP (94 +/- 3 mmHg, P < 0.005) which remained stable until the end of the study at 7 years (94 +/- 1 mmHg, P < 0.005 vs baseline). There was also a significant decrease in LVMI (131 +/- 6 g/m2, P < 0.05) after year 1 which continued to decrease until the end of the study reaching 98 +/- 6 g/m2 (P < 0.01 vs year 1 and baseline). Although Ccr remained stable after year 1, a significant decrease was observed after 7 years of follow-up (59 +/- 6 ml/min, P < 0.001 vs year 1 and baseline). CONCLUSIONS: ACE inhibition in hypertensive ADPKD patients provided long-term reversal of LVH in association with a mean 3.6 ml/min/year decline of Ccr. These preliminary results have potential important implications for cardiovascular and renal protection in ADPKD.