Turner, Stephen T.

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.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4‐week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: −9.6 ± 8.0 vs −5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: −18.7 ± 13.8 vs −13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (−17.0 ± 13.2/−9.6 ± 7.5 vs −7.0 ± 18.6/−6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.

Background Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. Methods 131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones (ACE, A-II, Bradykinin, ANP, BNP, and catecholamines), an echocardiogram for cardiac function and systolic PAP (PAPsys). Results Mean LVEF was 29% ∓ 12%, NYHA class 2 ∓ 1, age 56 ∓ 12 yr, BMI 28 ∓ 5 kg/m 2 . Forty-six patients (35%) were homozygous for the +9 allele, 58 (44%) were heterozygous (+9/-9) and 27 (21%) were homozygous for the -9 allele of the BDKRB2. PAPsys averaged 42 ∓ 13, 38 ∓ 12, and 35 ∓ 11 mmHg for +9/+9, +9/-9 and -9/-9, respectively (p = 0.03). There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in -9/-9 patients (9.5 ∓ 10.7, 7.1 ∓ 8.7, and 5.4 ∓ 6.4 U/L, respectively, p = 0.06). There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes. Conclusion These data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF.