Publications by authors named "Jovia L Nierenberg"

11 Publications

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Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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April 2021

Race modifies the association between animal protein metabolite 1-methylhistidine and blood pressure in middle-aged adults: the Bogalusa Heart Study.

J Hypertens 2020 12;38(12):2435-2442

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine.

Objective: Dietary factors mediate racial disparities in hypertension. However, the physiological mechanisms underlying this relationship are incompletely understood. We sought to assess the association between 1-methylhistidine (1-MH), a metabolite marker of animal protein consumption, and blood pressure (BP) in a community-based cohort of black and white middle-aged adults.

Methods: This analysis consisted of 655 participants of the Bogalusa Heart Study (25% black, 61% women, aged 34-58 years) who were not taking antihypertensive medication. Fasting serum 1-MH was measured using liquid chromatography-tandem mass spectroscopy. Animal food intakes were quantified by food-frequency questionnaires. Multivariable linear regression assessed the association between 1-MH and BP in combined and race-stratified analyses, adjusting for demographic, dietary, and cardiometabolic factors.

Results: A significant dose--response relationship was observed for the association of red meat (P-trend <0.01) and poultry (P-trend = 0.03) intake with serum 1-MH among all individuals. Serum 1-MH, per standard deviation increase, had a significant positive association with SBP (β=3.4 ± 1.6 mmHg, P = 0.04) and DBP (β=2.0 ± 1.1 mmHg, P = 0.05) in black participants, whereas no appreciable association was observed in white participants. Among a subgroup of black participants with repeat outcome measures (median follow-up = 3.0 years), one standard deviation increase in 1-MH conferred a 3.1 and 2.2 mmHg higher annual increase in SBP (P = 0.03) and DBP (P = 0.03), respectively.

Conclusion: Serum 1-MH associates with higher SBP and DBP in blacks, but not whites. These results suggest a utility for further assessing the role of dietary 1-MH among individuals with hypertension to help minimize racial disparities in cardiovascular health.
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December 2020

Serum metabolites associate with physical performance among middle-aged adults: Evidence from the Bogalusa Heart Study.

Aging (Albany NY) 2020 06 1;12(12):11914-11941. Epub 2020 Jun 1.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.

Age-related declines in physical performance predict cognitive impairment, disability, chronic disease exacerbation, and mortality. We conducted a metabolome-wide association study of physical performance among Bogalusa Heart Study participants. Bonferroni corrected multivariate-adjusted linear regression was employed to examine cross-sectional associations between single metabolites and baseline gait speed (N=1,227) and grip strength (N=1,164). In a sub-sample of participants with repeated assessments of gait speed (N=282) and grip strength (N=201), significant metabolites from the cross-sectional analyses were tested for association with change in physical performance over 2.9 years of follow-up. Thirty-five and seven metabolites associated with baseline gait speed and grip strength respectively, including six metabolites that associated with both phenotypes. Three metabolites associated with preservation or improvement in gait speed over follow-up, including: sphingomyelin (40:2) (P=2.6×10) and behenoyl sphingomyelin (d18:1/22:0) and ergothioneine (both P<0.05). Seven metabolites associated with declines in gait speed, including: 1-carboxyethylphenylalanine (P=8.8×10), and N-acetylaspartate, N-formylmethionine, S-adenosylhomocysteine, N-acetylneuraminate, N2,N2-dimethylguanosine, and gamma-glutamylphenylalanine (all P<0.05). Two metabolite modules reflecting sphingolipid and bile acid metabolism associated with physical performance (minimum P=7.6×10). These results add to the accumulating evidence suggesting an important role of the human metabolome in physical performance and specifically implicate lipid, nucleotide, and amino acid metabolism in early physical performance decline.
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June 2020

Pseudouridine and N-formylmethionine associate with left ventricular mass index: Metabolome-wide association analysis of cardiac remodeling.

J Mol Cell Cardiol 2020 03 11;140:22-29. Epub 2020 Feb 11.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America. Electronic address:

Background: Heart failure (HF) is the fastest growing form of cardiovascular disease both nationally and globally, underlining a need to phenotype subclinical HF intermediaries to improve primary prevention.

Objectives: We aimed to identify novel metabolite associations with left ventricular (LV) remodeling, one upstream HF intermediary, among a community-based cohort of individuals.

Methods: We examined 1052 Bogalusa Heart Study participants (34.98% African American, 57.41% female, aged 33.6-57.5 years). Measures of LV mass and relative wall thickness (RWT) were obtained using two-dimensional-guided echocardiographic measurements via validated eqs. LV mass was indexed to height to calculate left ventricular mass index (LVMI). Untargeted metabolomic analysis of fasting serum samples was conducted. In combined and ethnicity-stratified analyses, multivariable linear and multinomial logistic regression models tested the associations of metabolites with the continuous LVMI and RWT and categorical LV geometry phenotypes, respectively, after adjusting for demographic and traditional cardiovascular disease risk factors.

Results: Pseudouridine (B = 1.38; p = 3.20 × 10) and N-formylmethionine (B = 1.65; 3.30 × 10) were significantly associated with LVMI in the overall sample as well significant in Caucasians, with consistent effect direction and nominal significance (p < .05) in African Americans. Upon exclusion of individuals with self-report myocardial infarction or congestive HF, we similarly observed a 1.33 g/m and 1.52 g/m higher LVMI for each standard deviation increase in pseudouridine and N-formylmethionine, respectively. No significant associations were observed for metabolites with RWT or categorical LV remodeling outcomes.

Conclusions: The current analysis identified novel associations of pseudouridine and N-formylmethionine with LVMI, suggesting that mitochondrial-derived metabolites may serve as early biomarkers for LV remodeling and subclinical HF.
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March 2020

An untargeted metabolomics study of blood pressure: findings from the Bogalusa Heart Study.

J Hypertens 2020 07;38(7):1302-1311

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana.

Objective: To identify novel and confirm previously reported metabolites associated with SBP, DBP, and hypertension in a biracial sample of Bogalusa Heart Study (BHS) participants.

Methods: We employed untargeted, ultra-high performance liquid chromatography tandem mass spectroscopy metabolomics profiling among 1249 BHS participants (427 African-Americans and 822 whites) with BP and covariable data collected during the 2013 to 2016 visit cycle. A total of 1202 metabolites were tested for associations with continuous and binary BP phenotypes using multiple linear and logistic regression models, respectively, in overall and race-stratified analyses.

Results: A total of 24 novel metabolites robustly associated with BP, achieving Bonferroni-corrected P less than 4.16 × 10 in the overall analysis and consistent effect sizes across race groups. The identified metabolites included three amino acid and nucleotide metabolites from histidine, pyrimidine, or tryptophan metabolism sub-pathways, seven cofactor and vitamin or xenobiotic metabolites from the ascorbate and aldarate metabolism, bacterial/fungal, chemical, and food component sub-pathways, 10 lipid metabolites from the eicosanoid, phosphatidylcholine, phosphatidylethanolamine, and sphingolipid metabolism sub-pathways, and four still unnamed metabolites. Six previously described metabolites were robustly confirmed by our study (Bonferroni-corrected P < 4.95 × 10 and consistent effect directions across studies). Furthermore, previously reported metabolites for SBP, DBP, and hypertension demonstrated 5.92-fold, 4.77-fold, and 4.54-fold enrichment for nominally significant signals in the BHS (P = 3.08 × 10, 5.93 × 10, and 2.30 × 10, respectively).

Conclusion: In aggregate, our study provides new information about potential molecular mechanisms underlying BP regulation. We also demonstrate reproducibility of findings across studies despite differences in study populations and metabolite profiling methods.
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July 2020

Novel Findings From a Metabolomics Study of Left Ventricular Diastolic Function: The Bogalusa Heart Study.

J Am Heart Assoc 2020 02 29;9(3):e015118. Epub 2020 Jan 29.

Department of Epidemiology Tulane University School of Public Health and Tropical Medicine New Orleans LA.

Background Diastolic dysfunction is one important causal factor for heart failure with preserved ejection fraction, yet the metabolic signature associated with this subclinical phenotype remains unknown. Methods and Results Ultra-high-performance liquid chromatography-tandem mass spectroscopy was used to conduct untargeted metabolomic analysis of fasting serum samples in 1050 white and black participants of the BHS (Bogalusa Heart Study). After quality control, 1202 metabolites were individually tested for association with 5 echocardiographic measures of left ventricular diastolic function using multivariable-adjusted linear regression. Measures of left ventricular diastolic function included the ratio of peak early filling velocity to peak late filling velocity, ratio of peak early filling velocity to mitral annular velocity, deceleration time, isovolumic relaxation time, and left atrial maximum volume index (LAVI). Analyses adjusted for multiple cardiovascular disease risk factors and used Bonferroni-corrected alpha thresholds. Eight metabolites robustly associated with left ventricular diastolic function in the overall population and demonstrated consistent associations in white and black study participants. N-formylmethionine (B=0.05; =1.50×10); 1-methylhistidine (B=0.05; =1.60×10); formiminoglutamate (B=0.07; =5.60×10); N2, N5-diacetylornithine (B=0.05; =1.30×10); N-trimethyl 5-aminovalerate (B=0.04; =5.10×10); 5-methylthioadenosine (B=0.04; =1.40×10); and methionine sulfoxide (B=0.04; =3.80×10) were significantly associated with the natural log of the ratio of peak early filling velocity to mitral annular velocity. Butyrylcarnitine (B=3.18; =2.10×10) was significantly associated with isovolumic relaxation time. Conclusions The current study identified novel findings of metabolite associations with left ventricular diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in heart failure with preserved ejection fraction pathogenesis.
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February 2020

Novel associations between blood metabolites and kidney function among Bogalusa Heart Study and Multi-Ethnic Study of Atherosclerosis participants.

Metabolomics 2019 11 13;15(12):149. Epub 2019 Nov 13.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2000, New Orleans, LA, 70112, USA.

Introduction: Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD.

Objectives: The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data.

Methods: Untargeted ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th-95th percentile: 66.0-119.6 mL/min/1.73 m). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th-95th percentile: 43.5-105.0 mL/min/1.73 m). All analyses used Bonferroni-corrected alpha thresholds.

Results: Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of CHO and CHO(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites.

Conclusion: The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers.
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November 2019

Novel serum metabolites associate with cognition phenotypes among Bogalusa Heart Study participants.

Aging (Albany NY) 2019 07;11(14):5124-5139

Department of Epidemiology, Tulane University, New Orleans, LA 70112, USA.

Background: Metabolomics study provides an opportunity to identify novel molecular determinants of altered cognitive function.

Methods: During 2013 to 2016 Bogalusa Heart Study (BHS) visit, 1,177 participants underwent untargeted, ultrahigh performance liquid chromatography-tandem mass spectroscopy metabolomics profiling. Global cognition and five cognition domains were also assessed. The cross-sectional associations of single metabolites with cognition were tested using multiple linear regression models. Weighted correlation network analysis was used to examine the covariable-adjusted correlations of modules of co-abundant metabolites with cognition. Analyses were conducted in the overall sample and according to both ethnicity and sex.

Results: Five known metabolites and two metabolite modules robustly associated with cognition across overall and stratified analyses. Two metabolites were from lipid sub-pathways including fatty acid metabolism [9-hydroxystearate; minimum P-value (min-P)=1.11×10], and primary bile acid metabolism (glyco-alpha-muricholate; min-P=4.10×10). One metabolite from the glycogen metabolism sub-pathway (maltose; min-P=9.77×10), one from the polyamine metabolism sub-pathway (N-acetyl-isoputreanine; min-P=1.03×10), and one from the purine metabolism sub-pathway (7-methylguanine; min-P=1.19×10) were also identified. Two metabolite modules reflecting bile acid metabolism and androgenic steroids correlated with cognition (min-P=5.00×10 and 3.00×10, respectively).

Conclusion: The novel associations of 5 known metabolites and 2 metabolite modules with cognition provide insights into the physiological mechanisms regulating cognitive function.
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July 2019

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Nat Commun 2018 11 28;9(1):5052. Epub 2018 Nov 28.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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November 2018

Blood Pressure Genetic Risk Score Predicts Blood Pressure Responses to Dietary Sodium and Potassium: The GenSalt Study (Genetic Epidemiology Network of Salt Sensitivity).

Hypertension 2017 12 9;70(6):1106-1112. Epub 2017 Oct 9.

From the Department of Epidemiology (J.L.N., C.L., J.H., T.N.K.) and Department of Medicine (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, LA; Department of Epidemiology and Biostatistics, University of Georgia College of Public Health, Athens (C.L.); Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., X.L., J.L., X.W.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (C.C.G., D.C.R.).

We examined the association between genetic risk score (GRS) for blood pressure (BP), based on single nucleotide polymorphisms identified in previous BP genome-wide association study meta-analyses, and salt and potassium sensitivity of BP among participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). The GenSalt study was conducted among 1906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/d), 7-day high-sodium (307.8 mmol sodium/d), and 7-day high-sodium plus potassium (60 mmol potassium/d) intervention. BP was measured 9× at baseline and at the end of each intervention period using a random zero sphygmomanometer. Associations between systolic BP (SBP), diastolic BP, and mean arterial pressure GRS and respective SBP, diastolic BP, and mean arterial pressure responses to the dietary interventions were assessed using mixed linear regression models that accounted for familial dependencies and adjusted for age, sex, field center, body mass index, and baseline BP. As expected, baseline SBP, diastolic BP, and mean arterial pressure significantly increased per quartile increase in GRS (=2.7×10, 9.8×10, and 6.4×10, respectively). In contrast, increasing GRS quartile conferred smaller SBP, diastolic BP, and mean arterial pressure responses to the low-sodium intervention (=1.4×10, 0.02, and 0.06, respectively) and smaller SBP responses to the high-sodium and potassium interventions (=0.10 and 0.05). In addition, overall findings were similar when examining GRS as a continuous measure. Contrary to our initial hypothesis, we identified an inverse relationship between BP GRS and salt and potassium sensitivity of BP. These data may provide novel implications on the relationship between BP responses to dietary sodium and potassium and hypertension.
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December 2017