Digital Commons Network^™

Adult Asthma Associated With Roadway Density And Housing In Rural Appalachia: The Mountain Air Project (Map)., W Jay Christian, John Flunker, Beverly May, Susan Westneat, Wayne T Sanderson, Nancy Schoenberg, Steven R Browning

UK CARES Faculty Publications

BACKGROUND: Appalachian Kentucky is a rural area with a high prevalence of asthma among adults. The relative contribution of environmental exposures in the etiology of adult asthma in these populations has been understudied.

OBJECTIVE: This manuscript describes the aims, study design, methods, and characteristics of participants for the Mountain Air Project (MAP), and focuses on associations between small area environmental exposures, including roadways and mining operations, and lifetime and current asthma in adults.

METHODS: A cohort of residents, aged 21 and older, in two Kentucky counties, was enrolled in a community-based, cross-sectional study. Stratified cluster sampling was used to select …

Rare Coding Variants In Rcn3 Are Associated With Blood Pressure, Karen Y. He, Tanika N. Kelly, Heming Wang, Jingjing Liang, Luke Zhu, Brian E. Cade, Themistocles L. Assimes, Lewis C. Becker, Amber L. Beitelshees, Lawrence F. Bielak, Adam P. Bress, Jennifer A. Brody, Yen-Pei Christy Chang, Yi-Cheng Chang, Paul S. De Vries, Ravindranath Duggirala, Ervin R. Fox, Nora Franceschini, Anna L. Furniss, Yan Gao, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of …

A Cluster Randomized Controlled Trial For A Multi-Level, Clinic-Based Smoking Cessation Program With Women In Appalachian Communities: Study Protocol For The "Break Free" Program, Joanne G. Patterson, Tia N. Borger, Jessica L. Burris, Mark Conaway, Robert Klesges, Amie Ashcraft, Lindsay Hauser, Connie Clark, Lauren Wright, Sarah Cooper, Merry C. Smith, Mark B. Dignan, Stephenie Kennedy-Rea, Electra D. Paskett, Roger Anderson, Amy K. Ferketich

Psychology Faculty Publications

BACKGROUND: The cervical cancer burden is high among women living in Appalachia. Cigarette smoking, a cervical cancer risk factor, is also highly prevalent in this population. This project aims to increase smoking cessation among women living in Appalachia by embedding a smoking cessation program within a larger, integrated cervical cancer prevention program.

METHODS: The broader program, the Take CARE study, is a multi-site research collaborative designed to address three risk factors for cervical cancer incidence and mortality: tobacco use, human papillomavirus (HPV) infection, and cervical cancer screening. Break Free is a primary care clinic-based implementation program that aims to promote …

Transforming Obesity Prevention For Children (Topchild) Collaboration: Protocol For A Systematic Review With Individual Participant Data Meta-Analysis Of Behavioural Interventions For The Prevention Of Early Childhood Obesity, Kylie E. Hunter, Brittany J. Johnson, Lisa Askie, Rebecca K. Golley, Louise A. Baur, Ian C. Marschner, Rachael W. Taylor, Luke Wolfenden, Charles T. Wood, Seema Mihrshahi, Alison J. Hayes, Chris Rissel, Kristy P. Robledo, Denise A. O'Connor, David Espinoza, Lukas P. Staub, Paul Chadwick, Sarah Taki, Angie Barba, Sol Libesman, Ana Maria Linares

Nursing Faculty Publications

INTRODUCTION: Behavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and …

Unpacking The Behavioural Components And Delivery Features Of Early Childhood Obesity Prevention Interventions In The Topchild Collaboration: A Systematic Review And Intervention Coding Protocol, Brittany J. Johnson, Kylie E. Hunter, Rebecca K. Golley, Paul Chadwick, Angie Barba, Mason Aberoumand, Sol Libesman, Lisa Askie, Rachael W. Taylor, Kristy P. Robledo, Seema Mihrshahi, Denise A. O'Connor, Alison J. Hayes, Luke Wolfenden, Charles T. Wood, Louise A. Baur, Chris Rissel, Lukas P. Staub, Sarah Taki, Wendy Smith, Ana Maria Linares

Nursing Faculty Publications

INTRODUCTION: Little is known about how early (eg, commencing antenatally or in the first 12 months after birth) obesity prevention interventions seek to change behaviour and which components are or are not effective. This study aims to (1) characterise early obesity prevention interventions in terms of target behaviours, delivery features and behaviour change techniques (BCTs), (2) explore similarities and differences in BCTs used to target behaviours and (3) explore effectiveness of intervention components in preventing childhood obesity.

METHODS AND ANALYSIS: Annual comprehensive systematic searches will be performed in Epub Ahead of Print/MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, as well as …

Combined Driving: Task-Specific Position Impacts Grip Strength Of Equestrian Athletes, Michaela M. Keener, Kimberly I. Tumlin, Nicholas R. Heebner

Athletic Training and Clinical Nutrition Faculty Publications

BACKGROUND: Loss of hand strength is a predictor of mortality in aging populations. Despite reliance on the hands to participate in equestrian driving activity, no existing studies focus on associations of hand strength to athletic performance. Therefore, this study 1) established baseline handgrip of equestrian combined drivers in standing and task-specific positions, 2) determined endurance of task-specific handgrip, 3) compared handgrip strength to normative data, and 4) evaluated associations of handgrip and equestrian-specific variables.

METHODS: There were 51 combined drivers (9 males, 42 females) ages 21-78 who completed a survey, standing handgrip, and grip strength and endurance in a task-specific …

Genetic Contributors Of Incident Stroke In 10,700 African Americans With Hypertension: A Meta-Analysis From The Genetics Of Hypertension Associated Treatments And Reasons For Geographic And Racial Differences In Stroke Studies, Nicole D. Armstrong, Vinodh Srinivasasainagendra, Amit Patki, Rikki M. Tanner, Bertha A. Hidalgo, Hemant K. Tiwari, Nita A. Limdi, Ethan M. Lange, Leslie A. Lange, Donna K. Arnett, Marguerite R. Irvin

Epidemiology and Environmental Health Faculty Publications

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals.

Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs …

A Cross-Sectional Survey Of Potential Factors, Motivations, And Barriers Influencing Research Participation And Retention Among People Who Use Drugs In The Rural Usa, Angela T. Hetrick, April M. Young, Miriam R. Elman, Sarann Bielavitz, Rhonda L. Alexander, Morgan Brown, Elizabeth Needham Waddell, P. Todd Korthuis, Kathryn E. Lancaster

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: Despite high morbidity and mortality among people who use drugs (PWUD) in rural America, most research is conducted within urban areas. Our objective was to describe influencing factors, motivations, and barriers to research participation and retention among rural PWUD.

METHODS: We recruited 255 eligible participants from community outreach and community-based, epidemiologic research cohorts from April to July 2019 to participate in a cross-sectional survey. Eligible participants reported opioid or injection drug use to get high within 30 days and resided in high-needs rural counties in Oregon, Kentucky, and Ohio. We aggregated response rankings to identify salient influences, motivations, and …

A 6-Cpg Validated Methylation Risk Score Model For Metabolic Syndrome: The Hypergen And Goldn Studies, Bertha A. Hidalgo, Bre Minniefield, Amit Patki, Rikki Tanner, Minoo Bagheri, Hemant K. Tiwari, Donna K. Arnett, Marguerite Ryan Irvin

Epidemiology and Environmental Health Faculty Publications

There has been great interest in genetic risk prediction using risk scores in recent years, however, the utility of scores developed in European populations and later applied to non-European populations has not been successful. The goal of this study was to create a methylation risk score (MRS) for metabolic syndrome (MetS), demonstrating the utility of MRS across race groups using cross-sectional data from the Hypertension Genetic Epidemiology Network (HyperGEN, N = 614 African Americans (AA)) and the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, N = 995 European Americans (EA)). To demonstrate this, we first selected cytosine-guanine dinucleotides …

Genomics Of Postprandial Lipidomics In The Genetics Of Lipid-Lowering Drugs And Diet Network Study, Marguerite R. Irvin, May E. Montasser, Tobias Kind, Sili Fan, Dinesh K. Barupal, Amit Patki, Rikki M. Tanner, Nicole D. Armstrong, Kathleen A. Ryan, Steven A. Claas, Jeffrey R. O’Connell, Hemant K. Tiwari, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled …

Characterization Of Indoor Arenas Through An Anonymous Survey, Staci Mcgill, Morgan D. Hayes, Kimberly I. Tumlin, Robert Coleman

Biosystems and Agricultural Engineering Faculty Publications

Equine farms are building both stables for the horses to live in and additional facilities to train and work horses (Kidd et al., 1997). For many of these farms, an outdoor arena that has an all-weather footing is the first working facility built. During inclement weather the ability to train in the outdoor arenas is inhibited, which in turn means the trainers, riders, and farms lose income as money is only made when horses are working, training, and competing. Indoor arenas allow for horses to continue to be worked no matter the weather conditions. The equine industry contributes a total …

Framing Future Of Work Considerations Through Climate And Built Environment Assessment Of Volunteer Work Practices In The United States Equine Assisted Services, Kimberly I. Tumlin, Sa Liu, Jae-Hong Park

Epidemiology and Environmental Health Faculty Publications

The foundation of healthy workplace design is an understanding of work practices. Volunteers comprise the majority of the workforce in care centers using horses to address human health issues. Documentation is lacking on protections for worker well-being in equestrian microenvironments which are known to have the potential for dust exposures. Climate acts as a master variable in equestrian facility design and ventilation usage to address dust and temperature concerns. Using climate as an independent variable, our objective was to characterize space usage, safety, environmental control, and organizational practices through a national survey of equine assisted programs. We found that more …

Association Of Body Composition With Odds Of Breast Cancer By Molecular Subtype: Analysis Of The Mechanisms For Established And Novel Risk Factors For Breast Cancer In Nigerian Women (Mend) Study, Tomi Akinyemiju, Kelley Jones, Anjali Gupta, Taofik Oyekunle, Veeral Saraiya, April Deveaux, Omolola Salako, Allison Hall, Olusegun Alatise, Gabriel Ogun, Adewale Adeniyi, Omobolaji Ayandipo, Thomas Olajide, Olalekan Olasehinde, Olukayode Arowolo, Adewale Adisa, Oludolapo Afuwape, Aralola Olusanya, Aderemi Adegoke, Trygve O. Tollefsbol, Donna K. Arnett, H3 Africa Kidney Research Network, Adetola Daramola

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women.

METHODS: We estimated odds ratios (ORs) and 95% confidence intervals …

Association Of Manganese Biomarker Concentrations With Blood Pressure And Kidney Parameters Among Healthy Adolescents: Nhanes 2013–2018, Maria D. Politis, Jacob C. Freedman, Erin N. Haynes, Alison P. Sanders

Epidemiology and Environmental Health Faculty Publications

Deficiency or excess exposure to manganese (Mn), an essential mineral, may have potentially adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. We hypothesized that Mn concentrations were associated with poorer blood pressure (BP) and kidney parameters such as estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and albumin creatinine ratio (ACR). We conducted a cross-sectional analysis of 1931 healthy U.S. adolescents aged 12–19 years participating in National Health and Nutrition Examination Survey cycles 2013–2014, 2015–2016, and 2017–2018. Blood and urine Mn concentrations …

Analysis Of Genes (Tmem106b, Grn, Abcc9, Kcnmb2, And Apoe) Implicated In Risk For Late-Nc And Hippocampal Sclerosis Provides Pathogenetic Insights: A Retrospective Genetic Association Study, Adam J. Dugan, Peter T. Nelson, Yuriko Katsumata, Lincoln M. P. Shade, Kevin L. Boehme, Merilee A. Teylan, Matthew D. Cykowski, Shubhabrata Mukherjee, John S. K. Kauwe, Timothy J. Hohman, Julie A. Schneider, Alzheimer’S Disease Genetics Consortium, David W. Fardo

Biostatistics Faculty Publications

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory …

Associations Of Circulating Dimethylarginines With The Metabolic Syndrome In The Framingham Offspring Study, Ibrahim Musa Yola, Carlee Moser, Meredith S. Duncan, Edzard Schwedhelm, Dorothee Atzler, Renke Maas, Juliane Hannemann, Rainer H. Böger, Ramachandran S. Vasan, Vanessa Xanthakis

Biostatistics Faculty Publications

BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively.

METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study …

Apobec Mutagenesis Is Concordant Between Tumor And Viral Genomes In Hpv-Positive Head And Neck Squamous Cell Carcinoma, Daniel L. Faden, Krystle A. Lang Kuhs, Maoxuan Lin, Adam Langenbucher, Maisa Pinheiro, Meredith Yeager, Michael Cullen, Joseph F. Boland, Mia Steinberg, Sara Bass, James S. Lewis, Michael S. Lawrence, Robert L. Ferris, Lisa Mirabello

Epidemiology and Environmental Health Faculty Publications

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per …

Predictors Of Chronic Opioid Therapy In Medicaid Beneficiaries With Hiv Who Initiated Antiretroviral Therapy, Gyeon Oh, Emily S. Brouwer, Erin L. Abner, David W. Fardo, Patricia R. Freeman, Chris Delcher, Daniela C. Moga

Epidemiology and Environmental Health Faculty Publications

The factors associated with chronic opioid therapy (COT) in patients with HIV is understudied. Using Medicaid data (2002-2009), this retrospective cohort study examines COT in beneficiaries with HIV who initiated standard combination anti-retroviral therapy (cART). We used generalized estimating equations on logistic regression models with backward selection to identify significant predictors of COT initiation. COT was initiated among 1014 out of 9615 beneficiaries with HIV (male: 10.4%; female: 10.7%). Those with older age, any malignancy, Hepatitis C infection, back pain, arthritis, neuropathy pain, substance use disorder, polypharmacy, (use of) benzodiazepines, gabapentinoids, antidepressants, and prior opioid therapies were positively associated with …

Longitudinal Pre-Exposure Prophylaxis (Prep) Acceptability, Initiation And Adherence Among Criminal Justice-Involved Adults In The Usa: The Southern Prep Cohort Study (Specs) Protocol, Katherine Lemasters, Carrie B. Oser, Mariah Cowell, Katie Mollan, Kathryn Nowotny, Lauren Brinkley-Rubinstein

Sociology Faculty Publications

INTRODUCTION: HIV prevalence among criminal justice (CJ)-involved adults is five times higher than the general population. Following incarceration, CJ-involved individuals experience multilevel barriers to HIV prevention. Pre-exposure prophylaxis (PrEP) is a widely available, daily medication efficacious in preventing HIV. Little is known about PrEP knowledge, acceptability, initiation and sustained use among CJ-involved persons or about how these outcomes vary by multilevel factors. The Southern Pre-Exposure Prophylaxis Study (SPECS) will investigate barriers and facilitators for PrEP initiation and sustained use among CJ-involved adults, building a foundation for PrEP interventions for this underserved population.

METHODS AND ANALYSIS: SPECS uses a mixed-methods sequential …

Association Of Nonacute Opioid Use And Cardiovascular Diseases: A Scoping Review Of The Literature, Jade H. Singleton, Erin L. Abner, Peter D. Akpunonu, Anna M. Kucharska-Newton

Epidemiology and Environmental Health Faculty Publications

BACKGROUND

In this scoping review, we identified and reviewed 23 original articles from the PubMed database that investigated the relationship between nonacute opioid use (NOU) and cardiovascular outcomes.

METHODS AND RESULTS

We defined NOU to include both long-term opioid therapy and opioid use disorder. We summarized the association between NOU and 5 classes of cardiovascular disease, including infective endocarditis, coronary heart disease (including myocardial infarction), congestive heart failure, cardiac arrythmia (including cardiac arrest), and stroke. The most commonly studied outcomes were coronary heart disease and infective endocarditis. There was generally consistent evidence of a positive association between community prevalence of …

Identification Of Novel And Rare Variants Associated With Handgrip Strength Using Whole Genome Sequence Data From The Nhlbi Trans-Omics In Precision Medicine (Topmed) Program, Chloé Sarnowski, Han Chen, Mary L. Biggs, Sylvia Wassertheil-Smoller, Jan Bressler, Marguerite R. Irvin, Kathleen A. Ryan, David Karasik, Donna K. Arnett, L. Adrienne Cupples, David W. Fardo, Stephanie M. Gogarten, Benjamin D. Heavner, Deepti Jain, Hyun Min Kang, Charles Kooperberg, Arch G. Mainous, Braxton D. Mitchell, Alanna C. Morrison, Jeffrey R. O'Connell

Epidemiology and Environmental Health Faculty Publications

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant …

Factors That Influence Enrollment In Syringe Services Programs In Rural Areas: A Qualitative Study Among Program Clients In Appalachian Kentucky, Umedjon Ibragimov, Katherine E. Cooper, Evan Batty, April M. Ballard, Monica Fadanelli, Skylar B. Gross, Emma M. Klein, Scott Lockard, April M. Young, Hannah L. F. Cooper

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: Enrolling sufficient number of people who inject drugs (PWID) into syringe services programs (SSP) is important to curtail outbreaks of drug-related harms. Still, little is known about barriers and facilitators to SSP enrollment in rural areas with no history of such programs. This study's purpose was to develop a grounded theory of the role of the risk environment and individual characteristics of PWID in shaping SSP enrollment in rural Kentucky.

METHODS: We conducted one-on-one semi-structured interviews with 41 clients of 5 SSPs that were established in rural counties in Appalachian Kentucky in 2017-2018. Interviews covered PWID needs, the process …

Serological Survey Of Leptospira Infection In Arabian Horses In Poland, Bernard Wasiński, Katarzyna Paschalis-Trela, Jan Trela, Michał Czopowicz, Jerzy Kita, Monika Żychska, Anna Cywińska, Iwona Markowska-Daniel, Craig N. Carter, Lucjan Witkowski

Veterinary Diagnostic Laboratory Faculty Publications

Leptospirosis is one of the most common zoonotic infections worldwide, including in most livestock, some companion animals, horses, wildlife, and humans. Epidemiological estimation of its prevalence in all species is difficult due to the variety of clinical presentations and challenges regarding laboratory diagnosis. The purpose of this study was to measure the seroprevalence of leptospiral infection in Arabian horses kept in the largest breeding farms in Poland, representing over 15% of the Polish Arabian horse population. Leptospira antibodies were detected by MAT (cut-off 1:100) in 33.2% of serum samples (204 of 615 animals) (CI 95%: 29.6–37.0%), most frequently reacting with …

Epigenome-Wide Association Study Of Kidney Function Identifies Trans-Ethnic And Ethnic-Specific Loci, Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. Mccartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Mesa Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear …

Age And Sex Are Associated With The Plasma Lipidome: Findings From The Goldn Study, Emily Slade, Marguerite R. Irvin, Kevin Xie, Donna K. Arnett, Steven A. Claas, Tobias Kind, David W. Fardo, Gregory A. Graf

Biostatistics Faculty Publications

Background
Developing an understanding of the biochemistry of aging in both sexes is critical for managing disease throughout the lifespan. Lipidomic associations with age and sex have been reported, but prior studies are limited by measurements in serum rather than plasma or by participants taking lipid-lowering medications.

Methods
Our study included lipidomic data from 980 participants aged 18–87 years old from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN). Participants were off lipid-lowering medications for at least 4 weeks, and signal intensities of 413 known lipid species were measured in plasma. We examined linear age and sex associations with …

Protecting P-Glycoprotein At The Blood-Brain Barrier From Degradation In An Alzheimer's Disease Mouse Model, Yujie Ding, Yu Zhong, Andrea Baldeshwiler, Erin L. Abner, Björn Bauer, Anika M. S. Hartz

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Failure to clear Aβ from the brain is partly responsible for Aβ brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aβ across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp). In AD, P-gp levels are reduced, which contributes to impaired Aβ brain clearance. However, the mechanism responsible for decreased P-gp levels is poorly understood and there are no strategies available to protect P-gp. We previously demonstrated in isolated brain capillaries ex vivo that human Aβ40 (hAβ40) triggers P-gp degradation by activating the ubiquitin-proteasome pathway. In this pathway, hAβ40 initiates P-gp ubiquitination, leading to internalization and …

Whole-Exome Sequencing And Hipsc Cardiomyocyte Models Identify Myrip, Trappc11, And Slc27a6 Of Potential Importance To Left Ventricular Hypertrophy In An African Ancestry Population, Marguerite R. Irvin, Praful Aggarwal, Steven A. Claas, Lisa De Las Fuentes, Anh N. Do, C. Charles Gu, Andrea Matter, Benjamin S. Olson, Amit Patki, Karen Schwander, Joshua D. Smith, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Amy J. Turner, Deborah A. Nickerson, Dabeeru C. Rao, Ulrich Broeckel, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: 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.

Methods and Results: We conducted an exome-wide association study of LV mass (LVM) adjusted to height^2.7, 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 …

Aberrant Azin2 And Polyamine Metabolism Precipitates Tau Neuropathology, Leslie A. Sandusky-Beltran, Andrii Kovalenko, Devon S. Placides, Kevin Ratnasamy, Chao Ma, Jerry B. Hunt, Huimin Liang, John Ivan T. Calahatian, Camilla Michalski, Margaret Fahnestock, Laura J. Blair, April L. Darling, Jeremy D. Baker, Sarah N. Fontaine, Chad A. Dickey, Joshua J. Gamsby, Kevin R. Nash, Erin L. Abner, Maj-Linda B. Selenica, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to …

Sex, Diabetes Status And Cognition: Findings From The Study Of Longevity In Diabetes, Chris Moran, Paola Gilsanz, Michal S. Beeri, Rachel A. Whitmer, Mary E. Lacy

Epidemiology and Environmental Health Faculty Publications

INTRODUCTION: Women comprise two-thirds of people with dementia, making female sex a significant dementia risk factor. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are known dementia risk factors with an increasing global incidence. Understanding whether subtle sex differences persist in cognitive function prior to dementia in the context of diabetes may help elucidate the magnitude of sex effects on dementia risk.

RESEARCH DESIGN AND METHODS: We examined cross-sectional data from the Study of Longevity in Diabetes (SOLID), a prospective cohort study of members of Kaiser Permanente Northern California aged 60 years and older with T1D (n=758), T2D …

The Association Of Circulating Amylin With Β-Amyloid In Familial Alzheimer's Disease, Han Gia Ly, Nirmal Verma, Savita Sharma, Deepak Kotiya, Sanda Despa, Erin L. Abner, Peter T. Nelson, Gregory A. Jicha, Donna M. Wilcock, Larry B. Goldstein, Rita Guerreiro, José Brás, Angela J. Hanson, Suzanne Craft, Andrew J. Murray, Geert Jan Biessels, Claire Troakes, Henrik Zetterberg, John Hardy, Tammaryn Lashley, Alzheimer’S Disease Exome Sequencing Group, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

Introduction

This study assessed the hypothesis that circulating human amylin (amyloid‐forming) cross‐seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).

Methods

Evidence of amylin‐AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non‐APP/PS1 rats.

Results

Amylin‐Aβ cross‐seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected …