Publications by authors named "Lisa de Las Fuentes"

95 Publications

Resistance exercise training with protein supplementation improves skeletal muscle strength and improves quality of life in late adolescents and young adults with Barth syndrome: A pilot study.

JIMD Rep 2021 Nov 9;62(1):74-84. Epub 2021 Aug 9.

Program in Physical Therapy Washington University School of Medicine St. Louis Missouri USA.

Background: Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training (RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS.

Methods: Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health-related QOL were assessed pre-post intervention.

Results: RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass.

Conclusions: RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS.
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http://dx.doi.org/10.1002/jmd2.12244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574175PMC
November 2021

Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

HGG Adv 2021 Jan 31;2(1). Epub 2020 Oct 31.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
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http://dx.doi.org/10.1016/j.xhgg.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562625PMC
January 2021

Development of a Health Information Technology Tool for Behavior Change to Address Obesity and Prevent Chronic Disease Among Adolescents: Designing for Dissemination and Sustainment Using the ORBIT Model.

Front Digit Health 2021 10;3:648777. Epub 2021 Mar 10.

Institute for Public Health, Washington University in St. Louis, St. Louis, MO, United States.

Health information technology (HIT) has not been broadly adopted for use in outpatient healthcare settings to effectively address obesity in youth, especially among disadvantaged populations that face greater barriers to good health. A well-designed HIT tool can deliver behavior change recommendations and provide community resources to address this gap, and the Obesity-Related Behavioral Intervention Trials (ORBIT) model can guide its development and refinement. This article reports the application of the ORBIT model to (1) describe the characteristics and design of a novel HIT tool (the PREVENT tool) using behavioral theory, (2) illustrate the use of stakeholder-centered "designing for dissemination and sustainability" principles, and (3) discuss the practical implications and directions for future research. Two types of stakeholder engagement (customer discovery and user testing) were conducted with end users (outpatient healthcare teams). Customer discovery interviews ( = 20) informed PREVENT tool components and intervention targets by identifying (1) what healthcare teams (e.g., physicians, dietitians) identified as their most important "jobs to be done" in helping adolescents who are overweight/obese adopt healthy behaviors, (2) their most critical "pains" and "gains" related to overweight/obesity treatment, and (3) how they define success compared to competing alternatives. Interviews revealed the need for a tool to help healthcare teams efficiently deliver tailored, evidence-based behavior change recommendations, motivate patients, and follow-up with patients within the constraints of clinic schedules and workflows. The PREVENT tool was developed to meet these needs. It facilitates prevention discussions, delivers tailored, evidence-based recommendations for physical activity and food intake, includes an interactive map of community resources to support behavior change, and automates patient follow-up. Based on Self-Determination Theory, the PREVENT tool engages the patient to encourage competence and autonomy to motivate behavior change. The use of this intentional, user-centered design process should increase the likelihood of the intended outcomes (e.g., behavior change, weight stabilization/loss) and ultimately increase uptake, implementation success, and long-term results. After initial tool development, user-testing interviews ( = 13) were conducted using a think-aloud protocol that provided insight into users' (i.e., healthcare teams) cognitive processes, attitudes, and challenges when using the tool. Overall, the PREVENT tool was perceived to be useful, well-organized, and visually appealing.
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http://dx.doi.org/10.3389/fdgth.2021.648777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521811PMC
March 2021

Exploring contextual factors influencing the implementation of evidence-based care for hypertension in Rwanda: a cross-sectional study using the COACH questionnaire.

BMJ Open 2021 09 21;11(9):e048425. Epub 2021 Sep 21.

Cardiovascular Division, Department of Medicine, Washington University in St. Louis, St Louis, Missouri, USA

Importance: Hypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary.

Objective: To study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool.

Design: A cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training.

Setting: Three tertiary care hospitals in Rwanda.

Participants: Healthcare professionals (n=223).

Primary Outcomes And Measures: The COACH tool consists of 49 items with eight subscales: resources, community engagement, commitment to work, informal payment, leadership, work culture, monitoring services for action (5-point Likert Scale) and sources of knowledge (on a 0-1 scale). Four questions surveyed training on hypertension.

Results: Responders (n=223, 75% women; 56% aged 20-35 years) included nurses (n=142, 64%, midwives (n=42, 19%), primary care physicians (n=28, 13%) and physician specialists (n=11, 5%)). The subscales commitment to work, leadership, work culture and informal payment scored between 4.7 and 4.1 and the community engagement, monitoring services for action and organizational resources scored between 3.1 and 3.5. Sources of knowledge had a mean score of 0.6±0.3. While 73% reported having attended a didactic hypertension seminar in the past year, only 28% had received long-term training and 51% had <3-year experience working with hypertension care delivery. The majority (99%) indicated a need for additional training in hypertension care.

Conclusions: There is a need for increased and continuous training in Rwanda. Healthcare responders stated a commitment to work and reported supportive leadership, while acknowledging limited resources and no monitoring systems. The COACH tool provides contextual guidance to develop training strategies prior to the implementation of a sustainable hypertension care programme.
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http://dx.doi.org/10.1136/bmjopen-2020-048425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458329PMC
September 2021

Population sequencing data reveal a compendium of mutational processes in the human germ line.

Science 2021 08 12;373(6558):1030-1035. Epub 2021 Aug 12.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.
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http://dx.doi.org/10.1126/science.aba7408DOI Listing
August 2021

A risk assessment tool for resumption of research activities during the COVID-19 pandemic for field trials in low resource settings.

BMC Med Res Methodol 2021 04 12;21(1):68. Epub 2021 Apr 12.

Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, USA.

Rationale: The spread of severe acute respiratory syndrome coronavirus-2 has suspended many non-COVID-19 related research activities. Where restarting research activities is permitted, investigators need to evaluate the risks and benefits of resuming data collection and adapt procedures to minimize risk.

Objectives: In the context of the multicountry Household Air Pollution Intervention (HAPIN) trial conducted in rural, low-resource settings, we developed a framework to assess the risk of each trial activity and to guide protective measures. Our goal is to maximize the integrity of reseach aims while minimizing infection risk based on the latest scientific understanding of the virus.

Methods: We drew on a combination of expert consultations, risk assessment frameworks, institutional guidance and literature to develop our framework. We then systematically graded clinical, behavioral, laboratory and field environmental health research activities in four countries for both adult and child subjects using this framework. National and local government recommendations provided the minimum safety guidelines for our work.

Results: Our framework assesses risk based on staff proximity to the participant, exposure time between staff and participants, and potential viral aerosolization while performing the activity. For each activity, one of four risk levels, from minimal to unacceptable, is assigned and guidance on protective measures is provided. Those activities that can potentially aerosolize the virus are deemed the highest risk.

Conclusions: By applying a systematic, procedure-specific approach to risk assessment for each trial activity, we were able to protect our participants and research team and to uphold our ability to deliver on the research commitments we have made to our staff, participants, local communities, and funders. This framework can be tailored to other research studies conducted in similar settings during the current pandemic, as well as potential future outbreaks with similar transmission dynamics. The trial is registered with clinicaltrials.gov NCT02944682 on October 26. 2016 .
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http://dx.doi.org/10.1186/s12874-021-01232-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040756PMC
April 2021

Ultrasound Core Laboratory for the Household Air Pollution Intervention Network Trial: Standardized Training and Image Management for Field Studies Using Portable Ultrasound in Fetal, Lung, and Vascular Evaluations.

Ultrasound Med Biol 2021 06 1;47(6):1506-1513. Epub 2021 Apr 1.

Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine, Washington University in St. Louis, Missouri, USA.

Ultrasound Core Laboratories (UCL) are used in multicenter trials to assess imaging biomarkers to define robust phenotypes, to reduce imaging variability and to allow blinded independent review with the purpose of optimizing endpoint measurement precision. The Household Air Pollution Intervention Network, a multicountry randomized controlled trial (Guatemala, Peru, India and Rwanda), evaluates the effects of reducing household air pollution on health outcomes. Field studies using portable ultrasound evaluate fetal, lung and vascular imaging endpoints. The objective of this report is to describe administrative methods and training of a centralized clinical research UCL. A comprehensive administrative protocol and training curriculum included standard operating procedures, didactics, practical scanning and written/practical assessments of general ultrasound principles and specific imaging protocols. After initial online training, 18 sonographers (three or four per country and five from the UCL) participated in a 2 wk on-site training program. Written and practical testing evaluated ultrasound topic knowledge and scanning skills, and surveys evaluated the overall course. The UCL developed comprehensive standard operating procedures for image acquisition with a portable ultrasound system, digital image upload to cloud-based storage, off-line analysis and quality control. Pre- and post-training tests showed significant improvements (fetal ultrasound: 71% ± 13% vs. 93% ± 7%, p < 0.0001; vascular lung ultrasound: 60% ± 8% vs. 84% ± 10%, p < 0.0001). Qualitative and quantitative feedback showed high satisfaction with training (mean, 4.9 ± 0.1; scale: 1 = worst, 5 = best). The UCL oversees all stages: training, standardization, performance monitoring, image quality control and consistency of measurements. Sonographers who failed to meet minimum allowable performance were identified for retraining. In conclusion, a UCL was established to ensure accurate and reproducible ultrasound measurements in clinical research. Standardized operating procedures and training are aimed at reducing variability and enhancing measurement precision from study sites, representing a model for use of portable digital ultrasound for multicenter field studies.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054758PMC
June 2021

Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify , , and of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population.

Front Genet 2021 19;12:588452. Epub 2021 Feb 19.

College of Public Health, University of Kentucky, Lexington, KY, United States.

: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. We conducted an exome-wide association study of LV mass (LVM) adjusted to height, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (), trafficking protein particle complex 11 (), and solute carrier family 27 member 6 ()] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. knockdowns showed a significant decrease in atrial natriuretic factor () and brain natriuretic peptide () expression. Knockdowns of the heart long chain fatty acid (FA) transporter resulted in downregulated caveolin 3 () expression, which has been linked to hypertrophic phenotypes in animal models. Finally, knockdown was linked to deficient calcium handling. : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.
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http://dx.doi.org/10.3389/fgene.2021.588452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933688PMC
February 2021

Lifestyle Risk Score: handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions.

Eur J Hum Genet 2021 05 26;29(5):839-850. Epub 2021 Jan 26.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to "benchmark" results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to "benchmark" results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.
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http://dx.doi.org/10.1038/s41431-021-00808-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110957PMC
May 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

A Risk Assessment Tool for Resumption of Research Activities During the COVID-19 Pandemic.

Res Sq 2020 Nov 12. Epub 2020 Nov 12.

National Institutes of Health.

Rationale: The spread of severe acute respiratory syndrome coronavirus-2 has suspended many non-COVID-19 related research activities. Where restarting research activities is permitted, investigators need to evaluate the risks and benefits of resuming data collection and adapt procedures to minimize risk.

Objectives: In the context of the multicountry Household Air Pollution Intervention (HAPIN) trial, we developed a framework to assess the risk of each trial activity and to guide protective measures. Our goal is to maximize integrity of reseach aims while minimizing infection risk based on the latest understanding of the virus.

Methods: We drew on a combination of expert consultations, risk assessment frameworks, institutional guidance and literature to develop our framework. We then systematically graded clinical, behavioral, laboratory and field environmental health research activities in four countries for both adult and child subjects using this framework.

Results: Our framework assesses risk based on staff proximity to the participant, exposure time between staff and participants, and potential aerosolization while performing the activity. One of of four risk levels, from minimal to unacceptable, is assigned and guidance on protective measures is provided. Those activities which can potentially aerosolize the virus are deemed the highest risk.

Conclusions: By applying a systematic, procedure-specific approach to risk assessment for each trial activity, we can compare trial activities using the same criteria. This approach allows us to protect our participants and research team and to uphold our ability to deliver on the research commitments we have made to our participants, local communities, and funders. The trial is registered with clinicaltrials.gov (NCT02944682).
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http://dx.doi.org/10.21203/rs.3.rs-103997/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668754PMC
November 2020

The TDR MOOC training in implementation research: evaluation of feasibility and lessons learned in Rwanda.

Pilot Feasibility Stud 2020 15;6:66. Epub 2020 May 15.

2Regional Alliance for Sustainable Development (RASD) Rwanda, Kigali, Rwanda.

Background: Hypertension (HTN) affects nearly 1 billion people globally and is a major cause of morbidity and mortality. In low- and middle-income countries (LMICs), HTN represents an unmet health care gap that can be addressed by strengthening national health care systems. The National Heart, Lung, and Blood Institute recently funded the T4 Translation Research Capacity Building Initiative in Low Income Countries (TREIN) program to build capacity in dissemination and implementation (D&I) research in HTN in LMICs. The Special Programme for Research and Training in Tropical Diseases (TDR) at the World Health Organization (WHO) recently developed a massive open online course (MOOC) to train in D&I. Herein, we report on the use of the TDR WHO MOOC in D&I for the TREIN program in Rwanda, assessing feasibility of the MOOC and D&I competencies after MOOC training.

Methods: Participants in one-group MOOC training completed pre- and post-training questionnaires to assess dissemination and implementation (D&I) competency outcomes and feasibility. D&I competencies were measured by use of a scale developed for a US-based training program, with the change in competency scores assessed by paired test. Feasibility was measured by completion of homework and final project assignment and analyzed using descriptive statistics.

Results: Of the 92 trainees enrolled, 35 (38%) completed all MOOC components. D&I competency scores showed strong evidence of improvements from pre- to post-test. The full-scale average score improved by an average of 1.09 points, representing an effect size of 1.25 (CI 0.48-2.00); all four subscales also showed strong evidence of improvements. Trainees reported challenges to MOOC course completion that included technological issues (i.e., limited internet access) and competing demands (i.e., work, family).

Conclusions: In the context of LMIC training, the MOOC course was feasible and course completion showed improvement in D&I competency scores. While the program was designed with a focus on training for tropical diseases, there is potential for scalability to a wider audience of health care researchers, workers, administrators, and policymakers in LMIC interested in D&I research in non-communicable diseases.
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http://dx.doi.org/10.1186/s40814-020-00607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229620PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Identifying blood pressure loci whose effects are modulated by multiple lifestyle exposures.

Genet Epidemiol 2020 09 29;44(6):629-641. Epub 2020 Mar 29.

Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri.

Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene-multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome-wide gene-environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome-wide significant (p < 5 × 10 ) and 11 suggestive (p < 1 × 10 ) loci. Gene-environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1, and DAPK2. Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene-environment interaction analysis can identify additional loci missed by single lifestyle approaches.
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http://dx.doi.org/10.1002/gepi.22292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717887PMC
September 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome.

J Nucl Cardiol 2021 Aug 8;28(4):1649-1659. Epub 2019 Nov 8.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Background: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function.

Methods/results: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of O-water and 1-C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g·min, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g·min, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS.

Conclusions: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.
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http://dx.doi.org/10.1007/s12350-019-01933-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205570PMC
August 2021

Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2019 10 12;12(10):458-485. Epub 2019 Sep 12.

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.
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http://dx.doi.org/10.1161/HCG.0000000000000058DOI Listing
October 2019

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

Diabetol Metab Syndr 2019 29;11:61. Epub 2019 Jul 29.

1Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA.

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome.

Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment.

Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups.

Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting. ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.
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http://dx.doi.org/10.1186/s13098-019-0456-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664523PMC
July 2019

Dissemination and Implementation Program in Hypertension in Rwanda: Report on Initial Training and Evaluation.

Glob Heart 2019 06;14(2):135-141

Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and in low- and middle-income countries, and hypertension (HTN) is a major risk factor for CVD. Although effective evidence-based interventions for control of HTN in high-income countries exist, implementation of these in low- and middle-income countries has been challenging due to limited capacity and infrastructure for late-phase translational research. In Rwanda, the 2015 STEPS NCD (STEPwise Approach to Surveillance of Noncommunicable Diseases) risk survey reported an overall prevalence of HTN of 15% (95% confidence interval [CI]: 13.8 to 16.3) for those ages 15 to 64 years; prevalence increased with increasing age to 39% (95% CI: 35.7 to 43.1) for those ages 55 to 64 years; CVD was the third most common cause of mortality (7%). Suboptimal infrastructure and capacity in Rwanda hinders research and community knowledge for HTN control.

Objectives: To address the issue of suboptimal capacity to implement evidence-based interventions in HTN, this project was designed with the following objectives: 1) to develop a regional needs assessment of infrastructure for dissemination and implementation (D & I) strategies for HTN-CVD control; 2) to develop HTN-CVD research capacity through creation of countrywide resources such as core research facilities and training in the fields of HTN-CVD, D & I, and biostatistics; and 3) to engage and train multiple stakeholders in D & I and HTN-CVD evidence-based interventions.

Methods: A weeklong training program in HTN-CVD, biostatistics, and D & I was conducted in Rwanda in August 2018, and pre- and post-D & I training competency questionnaires were administered.

Results: Questionnaire results show a statistically significant increase in D & I knowledge and skills as a result of training (full scale pre- to post-test scores: 2.12 ± 0.78 vs. 3.94 ± 0.42; p < 0.0001).

Conclusions: Using principles of community engagement and train-the-trainer methods, we will continue to adapt guidelines and treatments for HTN-CVD developed in high-income countries to the context of Rwanda with the goal of establishing a sustainable platform to address the burden of disease from HTN-CVD.
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http://dx.doi.org/10.1016/j.gheart.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816501PMC
June 2019

The Promise of Selecting Individuals from the Extremes of Exposure in the Analysis of Gene-Physical Activity Interactions.

Hum Hered 2018 5;83(6):315-332. Epub 2019 Jun 5.

Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: Dichotomization using the lower quartile as cutoff is commonly used for harmonizing heterogeneous physical activity (PA) measures across studies. However, this may create misclassification and hinder discovery of new loci.

Objectives: This study aimed to evaluate the performance of selecting individuals from the extremes of the exposure (SIEE) as an alternative approach to reduce such misclassification.

Method: For systolic and diastolic blood pressure in the Framingham Heart Study, we performed a genome-wide association study with gene-PA interaction analysis using three PA variables derived by SIEE and two other dichotomization approaches. We compared number of loci detected and overlap with loci found using a quantitative PA variable. In addition, we performed simulation studies to assess bias, false discovery rates (FDR), and power under synergistic/antagonistic genetic effects in exposure groups and in the presence/absence of measurement error.

Results: In the empirical analysis, SIEE's performance was neither the best nor the worst. In most simulation scenarios, SIEE was consistently outperformed in terms of FDR and power. Particularly, in a scenario characterized by antagonistic effects and measurement error, SIEE had the least bias and highest power.

Conclusion: SIEE's promise appears limited to detecting loci with antagonistic effects. Further studies are needed to evaluate SIEE's full advantage.
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http://dx.doi.org/10.1159/000499711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662918PMC
October 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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http://dx.doi.org/10.1038/s41588-019-0378-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467258PMC
April 2019

Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome.

J Inherit Metab Dis 2019 05 11;42(3):480-493. Epub 2019 Apr 11.

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U- C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.
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http://dx.doi.org/10.1002/jimd.12094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483838PMC
May 2019

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

Am J Epidemiol 2019 06;188(6):1033-1054

Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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http://dx.doi.org/10.1093/aje/kwz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545280PMC
June 2019

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Nat Commun 2019 01 22;10(1):376. Epub 2019 Jan 22.

Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, 01246903, SP, Brazil.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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http://dx.doi.org/10.1038/s41467-018-08008-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342931PMC
January 2019
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