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Abstract BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and Results Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR ‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P <5×10 −8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS 2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P =4.17×10 −8 ). G‐allele carriers of HMGCS 2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P =0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10 −8 . HMGCS 2 , a part of the HMG ‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. Conclusions These results suggest that HMGCS 2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00246519 and NCT 01203852.

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

AbstractMRI has become an indispensable tool for brain volumetric studies, with the hippocampus an important region of interest. Automation of the MRI segmentation process has helped advance the field by facilitating the volumetric analysis of larger cohorts and more studies. FreeSurfer has emerged as the de facto standard tool for these analyses, but studies validating its output are all based on older versions. To characterize FreeSurfer's validity, we compare several versions of FreeSurfer software with traditional hand‐tracing. Using MRI images of 262 males and 402 females aged 38 to 84, we directly compare estimates of hippocampal volume from multiple versions of FreeSurfer, its hippocampal subfield routines, and our manual tracing protocol. We then use those estimates to assess asymmetry and atrophy, comparing performance of different estimators with each other and with brain atrophy measures. FreeSurfer consistently reports larger volumes than manual tracing. This difference is smaller in larger hippocampi or older people, with these biases weaker in version 6.0.0 than prior versions. All methods tested agree qualitatively on rightward asymmetry and increasing atrophy in older people. FreeSurfer saves time and money, and approximates the same atrophy measures as manual tracing, but it introduces biases that could require statistical adjustments in some studies.

Abstract Objective: Experimental models suggest estrogen has a renoprotective effect, but human studies show variable results. Our objective was to study the association of hormone therapy (HT) and albuminuria in postmenopausal women and to synthesize the results with outcomes from prior studies. Methods: We analyzed data from postmenopausal women who participated in the second study visit (2000-2004) of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. The exposure was self-reported HT use and the outcome was albuminuria (urine albumin-to-creatinine ratio >25 mg/g creatinine). We also conducted a systematic review and meta-analysis on the association of HT and urine protein in postmenopausal women. Continuous and dichotomous measures of protein excretion were converted to a standardized mean difference (SMD) for each study. Results: In the GENOA cohort ( n = 2,217), there were fewer women with albuminuria among HT users than nonusers (9% vs 19%, P < 0.001). HT use was associated with decreased odds of albuminuria (odds ratio 0.65, 95% confidence interval (CI), 0.45-0.95), after adjusting for significant differences in age, race, education, comorbidities, and the age at and cause of menopause. The SMD of the effect of HT on urine proteinuria/albuminuria in the randomized control trials ( n = 3) was 0.02 (95% CI, −0.29 to 0.33) and −0.13 (95% CI, −0.31 to 0.05) in the observational studies ( n = 9). There was significantly less albuminuria among HT users (SMD −0.15, 95% CI, −0.27 to −0.04) in the 9 studies that only reported albuminuria as an outcome and in the 10 studies with a comparator arm (SMD −0.15, 95% CI, −0.26 to −0.04). Conclusions: HT is associated with decreased odds of albuminuria, but some of the observed benefits may be related to reported outcomes, the presence of a comparator arm, and the type of study design.

Background Although hydrochlorothiazide ( HCTZ ) is a well‐established first‐line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure ( BP ) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. Methods and Results First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway ( P =5.8E‐05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC 3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C‐allele carriers had a better BP response to HCTZ versus noncarriers (∆ SBP /∆ DBP : −11.4/−6.9 versus −6.8/−3.5 mm Hg; ∆ SBP P =6.7E‐04; ∆ DBP P =4.8E‐04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC 3 genomic region significantly associated with the BP response to HCTZ ( P <0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP ‐response ( r =−0.42; P =7E‐03) and SBP ‐response ( r =−0.36; P =2E‐02). Conclusions This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC 3 is a potential determinant of the BP response to HCTZ . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Renal plasma flow, glomerular filtration rate, and cardiac output are traditionally indexed for body surface area by expressing these traits as per-surface-area ratios. Indexing is intended to remove interindividual variation attributable to differences in body size. Regression is an alternative method commonly used to adjust other biological traits for the effects of a covariate, such as body surface area. The purpose of this study was to compare the indexing and regression methods of adjusting renal plasma flow, glomerular filtration rate, and cardiac output for interindividual differences in body surface area. We estimated renal plasma flow by the clearance of p-aminohippurate, glomerular filtration rate by clearance of inulin, and cardiac output by thoracic electrical impedance in a sample of 78 unrelated females and 78 unrelated males (ages 20-49.9 yr) from the general population of Rochester, MN. The indexing method created negative dependencies of renal plasma flow and cardiac output on body surface area and failed to eliminate the positive dependency of glomerular filtration rate on body surface area. Moreover, indexing obscured differences in mean renal plasma flow between females and males and created differences in mean cardiac output between the genders. In contrast, the regression method consistently eliminated dependencies of each trait on body surface area and did not lead to inappropriate inferences about mean differences in these traits between females and males. We conclude that the indexing method of adjusting renal plasma flow, glomerular filtration rate, and cardiac output for interindividual differences in body surface area should be abandoned and replaced by use of the regression method.

Background The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure ( BP ) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker. Methods and Results A genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance ( P <1.0E‐05) were tested for replication in an external cohort, INVEST (International Verapamil‐ SR Trandolapril study). We also examined genome‐wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69–3.88, P =8.64E‐06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35–2.57, P =0.001) and approached genome‐wide significance in the meta‐analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63–2.86, P =8.60E‐08). Other genes in the region surrounding rs261316 ( ALDH1A2) include AQP9 and LIPC . Conclusions A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β‐blocker combination. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Background Whether the association of blood pressure ( BP ) during sleep (nocturnal BP ) with cognition differs by race is unknown. Methods and Results Participants in the GENOA (Genetic Epidemiology Network of Arteriopathy) Study underwent ambulatory BP measurements, brain magnetic resonance imaging, and cognitive function testing (the Rey Auditory Verbal Learning Test, the Digit Symbol Substitution Task, and the Trail Making Test Part B) between 2000 and 2007. We examined multivariable linear regression models of the nocturnal BP ‐cognition association. Among 755 participants (mean age, 63 years; 64% women; 42% self‐identified black race; 76% taking antihypertensive medication), mean nocturnal systolic BP ( SBP )/diastolic BP was 126/69 mm Hg, daytime SBP / diastolic BP level was 139/82 mm Hg, and mean reduction in SBP from day to night (dipping) was 9%. Among the entire sample, a race interaction was observed in Digit Symbol Substitution Task and Trail Making Test Part B (both P <0.15). Race‐stratified analyses showed that a 1‐ SD increase in nocturnal SBP levels was associated with poorer Digit Symbol Substitution Task and log‐transformed Trail Making Test Part B scores (unstandardized regression coefficient [95% confidence interval ]: −1.98 [−3.28 to −0.69] and 0.06 [0.004–0.12]; both P< 0.05) in black but not white individuals. Additional adjustments for white matter hyperintensity volumes or brain atrophy, measured via brain magnetic resonance imaging, did not change the results. Results were similar when nocturnal SBP dipping was assessed as the exposure, yet daytime SBP levels yielded no association with cognition. Conclusions Nocturnal SBP measurements may be useful in assessing the potential risk for lower cognitive function in middle‐aged and older adults, particularly in black individuals.