UW CHRU

Projects

Genomics of Sudden Cardiac Arrest Among African-Americans

Sudden cardiac arrest (SCA) is a major public health concern, particularly among African Americans where risk of cardiac arrest is higher than that of the general population, and survival is poor. Genomics of Sudden Cardiac Arrest Among African-Americans is a multi-center collaborative effort to identify and characterize genetic factors conferring susceptibility to SCA among African Americans. The project includes analysis of rare and common genetic variation and functional dissection of variants associated with SCA in mice and zebrafish. Few studies have examined the genetic risk factors for SCA among those of African descent, and this project aims to provide insights into SCA mechanisms and contribute to the development of novel drug therapies.

Atrial fibrillation burden, vascular disease of the brain, and cardiac MRI in MESA

Atrial fibrillation (AF) is a common arrhythmia that predisposes to devastating complications including stroke, faster cognitive decline, and dementia. It is not known whether AF episodes that occur without symptoms or AF episodes of longer duration increase risk for AF complications. Dr. Susan Heckbert is Principal Investigator on this project, which is conducted in the setting of the Multi-Ethnic Study of Atherosclerosis (MESA). Our research examines predictors and outcomes associated with AF duration and with AF that does not cause symptoms.

Rare Variants and NHLBI Traits in Deeply Phenotyped Cohorts

Rare variant genome-wide association studies (GWAS), using the Illumina ExomeChip, offer a chance to expand upon the results of common variant GWAS, which typically explain only 5-10% of genetic contribution to phenotypic variance. This study uses ExomeChip data from over 50,000 participants in the CHARGE Consortium in order to meet the significant sample size requirements for high quality analysis. Using the available ExomeChip coding-region genotype data from CHARGE, the primary aim is to discover novel candidate genes and putative functional variants for high-priority heart, lung and blood phenotypes in multi-ethnic cohorts.

Novel ECG Measures & Risk of SCD

Cardiovascular mortality and in particular, sudden cardiac death (SCD) is the leading cause of death in the adult US population. The overwhelming majority of SCD cases occur in subjects without known heart disease. Development of an intervention strategy to prevent SCD is urgently needed, and an essential first step is to determine the population at risk. An ECG is easily available, inexpensive and is a non-invasive tool carrying valuable information. CHRU researchers recently developed a 12-lead ECG SCD risk score which classifies patients into lower and higher SCD risk. This study aims to stratify patients into high-, intermediate-, and low-risk groups to improve classification compared to traditional coronary heart disease risk factors. It also uses genetic data from ARIC and CHS cohorts to identify novel heritable factors.

Epoxyeicosatrienoic acids (EETs) and cardiovascular and cardiometabolic diseases.

Two projects examine the role of circulating EETs in sudden cardiac death and diabetes and its cardiovascular complications. Collectively, these two RO1 grants will provide comprehensive information on the epidemiology of EETs in 3 large NHLBI-funded prospective studies, including association with cardiovascular and cardiometabolic disease outcomes. The projects will additionally investigate the molecular mechanism of EETs protection, discover pathways that regulate EET biosynthesis in cardiac tissue, and identify EETs-related pathways affected by diabetes, with the ultimate aim of identifying a novel, potentially modifiable drug target to improve cardiovascular health.

Genomics of Cardiac Electrical Activity and Arrhythmia

Abnormalities in cardiac electrical activity on the surface electrocardiogram can lead to cardiac arrhythmias and adverse outcomes (atrial fibrillation and sudden cardiac death), potentially resulting in the placement of cardiac pacemakers and/or defibrillators. This project seeks to identify whether genetic variation within biologically functional coding regions is associated with cardiac electrical activity and arrhythmia in the general population. To accomplish this, CHRU researchers have established the Cohorts for Heart and Aging Research in Genomic Epidemiology Exome Chip (CHARGE-EX) EKG consortium. CHARGE-EX encompasses 23 total cohorts and four ethnic groups (European, African, Hispanic, and East Asian descent individuals) with which to investigate rare variants and coding sequences for specific targeted genes. Additionally, researchers functionally validate and dissect these genetic findings in zebrafish.

Circulating Dietary & Metabolic Fatty Acids, Major Cardiovascular Outcomes, & Health Aging

While innovative research has begun to elucidate the role of individual fatty acids (FA) in human health, this work has historically focused on broad categories of dietary fats and relied on self-reported estimates from questionnaires. This CHRU study focuses on circulating FA biomarkers that provide objective measures of exposure to both dietary and metabolic FA. Researchers at CHRU have found several specific individual FA to be significantly associated with important cardiovascular disease outcomes, including congestive heart failure, atrial fibrillation, coronary heart disease and stroke. These FA are both those derived from diet and those derived from endogenous metabolic processes. This project is ongoing, with researchers elucidating the role of age on circulating FA.

Genetic Variation in Fatty Acid Metabolism and Sudden Cardiac Arrest

This study aims to examine whether common genetic variation in fatty acid (FA) metabolic pathways is associated with sudden cardiac arrest (SCA) risk in humans. This investigation involves genetic epidemiology, statistical genetics, molecular cardiology, genomics, and fatty acid metabolism with DNA and clinical data assembled over the past 18 years from several large populations. Investigators are examining blood samples and clinical data from 2600 European-American and 450 African-American SCA cases, primarily drawing from the Cardiac Arrest Blood Study Repository (CABS-R). Similarly, 2600 European American and 900 African-American controls will be drawn from two population-based studies of cardiovascular disease conducted in the same Washington State county as CABS-R.

Genome-Wide Study of Sudden Cardiac Arrest Risk in the Community

While there is evidence of familial aggregation, candidate genes, and the molecular genetics of inherited arrhythmias that genetic variation influences susceptibility to sudden cardiac arrest (SCA), at the beginning of this study the genetic architecture of SCA in the community remained unknown. Consequently, this study has aimed to identify novel associations of common genetic variation across the genome with SCA, using a case-control, genome-wide association study (GWAS), design. Through three stages, GWAS-SCA has conducted an initial GWAS search of approximately 4,500 cases and >20,000 controls (stage 1), a fine mapping of 100 genomic regions in 4500 SCA cases and matched controls(stage 2) and a replication in an independent sample of 1000 SCA cases and controls (stage 3). Analysis continues, providing insight into the mechanisms of SCA that may help to target interventions to reduce mortality from SCA.

The Cardiovascular Safety of Combination Therapies for Type 2 Diabetes Mellitus

Investigators are evaluating the cardiovascular safety of using oral diabetes medications after beginning insulin therapy for treatment of type 2 diabetes mellitus (DM). CHRU has previously studied the cardiovascular safety of other classes of medications within the setting of Kaiser Permanente. Investigators are leveraging these existing data to evaluate the cardiovascular safety of combinations of oral glucose-lowering therapies.

Prospective Meta-Analyses of Drug-Gene Interactions: CHARGE GWAS Consortium

The benefits of modern drug therapies can be maximized by avoiding some medications in patients who are genetically susceptible to adverse reactions or by selecting other medications for patients who are genetically likely to benefit. In this study investigators use genome-wide association studies (GWAS) methods to identify novel variants and pathways that affect drug response. Investigators have access to genome-wide data on more than 57,000 participants, and will be looking at reactions to an array of adverse drug effects. These include but are not limited to, sulfonylurea antidiabetic agents, thiazide diuretics, high-torsades-risk QT-prolonging drugs (selected antiarrhythmics, antihistamines, antibiotics, and antidepressants), and tri-cyclic or tetracyclic antidepressants.

Genomics and Pharmacodynamics of Statin-Related Rhabdomyolysis

Some statin users are susceptible to increased risk of myopathy or rhabdomyolysis. This study uses sequencing of the exons (coding regions of the genes) to identify and characterize the genetic determinants and biologic mechanisms that underlie this toxic response to lipid-lowering statin drugs.

Sphingolipids, diabetes and cardiovascular disease.

Type 2 diabetes has reached epidemic proportions and carries a high burden of cardiovascular morbidity and mortality. This project seeks to identify novel modifiable factors, plasma ceramide and sphingomyelin species, associated with risks of incident diabetes and diabetes-related cardiovascular disease. We measured sphingomyelins and ceramides with saturated fatty acids of different length, in plasma specimens from the Strong Heart Family Study. The discovery of precise sphingolipid species associated with diabetes and its cardiovascular complications will point to pathways that need to be targeted for future interventions.

Estrogens and Pharmacogenetic Risk of Venous Thrombosis in Postmenopausal Women

This comparative-safety study investigates venous thrombosis (VT) as a side-effect of short-term use of several oral estrogen that a commonly used to treat menopausal symptoms in peri- and post-menopausal women. Data on the comparative safety of oral estrogen products are limited and hinder women and their physicians from making evidence-based decisions when choosing an estrogen product. Researchers at CHRU investigate conjugated equine estrogen (CEE), estradiol (E2) and esterified estrogen (EE) usage in the setting of Kaiser Permanente, a large integrated healthcare organization here in Washington State. The study will provide high-quality data to begin to address important public health questions of women’s health.

Pharmacologic and Pharmacogenetic Associations with Recurrent Venous Thrombosis

Building on previous CHRU studies of incident venous thrombosis (VT), this project identifies risk factors for VT recurrence and to inform and guide treatment and prophylaxis decisions. We have followed a cohort of 2,800 incident VT events ages 30-89 for up to 11 years to monitor subsequent VT recurrences. One focus of the project is on statins and beta-blockers, which epidemiologic evidence suggests are associated with decreased risk of VT, but for which there are no data on VT recurrence. Additionally, CHRU is investigating potential biomarkers and drug-gene interactions and their associations with recurrent VT.

Clinical Coordinating Center for the Women's Health Initiative 2010-2015 Extension Study

CHRU investigator Dr. Susan Heckbert has been a co-investigator at the Women’s Health Initiative (see above) Clinical Coordinating Center (CCC) since 1995. As part of this project, she mentors new investigators within WHI and collaborates with CCC and other scientists to generate hypotheses and develop analytic plans to study scientific questions of interest in WHI. Dr. Heckbert also participates in data analysis, interpretation of results, and manuscript preparation.

Vitamin D Metabolism Related Genetic Variations and Developmental Origins of Cardiometabolic Risk

Mounting evidence supports the developmental origins of cardiometabolic risk. Additionally, low vitamin D levels are associated with cardiometabolic risk factors. This project aims to investigate the role of vitamin D-related genetic variations in developmental origins of cardiometabolic risk (including birth weight, obesity, insulin resistance, abnormal lipids and lipoproteins, and hypertension) using biomarker, genotyping, and gene expression measurements.

Dhulikhel Health Study - A Cohort Study in Dhulikhel, Nepal

The Dhulikhel Heart Study is a population-based longitudinal study following adults in the town of Dhulikhel in Nepal in order to study the risk and prevalence of cardiovascular diseases in the population, develop educational programs around cardiovascular disease (CVD) and its risk factors and implement screening for hypertension, diabetes and CVD within Dhulikhel. Cardiovascular disease is worsening in Nepal, with high levels of metabolic syndrome and untreated hypertension. Low-income and developing countries including Nepal have seen a marked rise in CVD with relatively little study to match, and The Dhulikhel Heart Study is one of the first longitudinal studies carried out in such settings.

Atrial Fibrillation in MESA and JHS

This project conducts research on a heart rhythm disorder, atrial fibrillation, using cohort study data and Medicare claims data from the Multi-Ethnic Study of Atherosclerosis and the Jackson Heart Study. We study whether extensive fat deposition around the heart is associated with enlargement of the left atrium over time and with the development of atrial fibrillation. We also lead an ECG/Arrhythmia Working Group to foster research on the epidemiology, pathophysiology, prevention, and treatment of heart rhythym disturbances.

Determinants of Activity, Diet, and Cardio-Metabolic Risk in American Indians

The burden of cardio-metabolic diseases is exceedingly high among American Indians (AIs). In the Strong Heart Family Study (SHFS), 84% of American Indians were overweight/obese, 39% had hypertension, and 51% had type 2 diabetes at baseline. Although physical activity and diet are major determinants of cardio-metabolic risk, the promotion of physical activity and a healthy diet has done little to lower the burden of cardio-metabolic diseases in AIs. This may, in part, be due to a poor understanding of the social determinants of health behaviors and cardio-metabolic risk factors in this population. Without understanding the social-contextual factors that contribute to health behaviors and risk factors, the implementation of sustainable interventions is difficult. Moreover, investments in interventions that do not recognize and address the underlying social-contextual factors that give rise to health behaviors and cardio-metabolic risk factors may be ineffective. The purpose of this award is to: (1) better understand the social determinants of physical activity, diet, and obesity-related cardio-metabolic risk factors; (2) integrate findings from social, physical activity, nutritional and cardiovascular epidemiology to inform the development of targeted a community-based culturally-appropriate pilot intervention for cardio-metabolic disease prevention among AIs.

Cardiovascular, Pulmonary and Hematological Disease in HIV: Prevention and Treatment

Dramatic advances in treatments for HIV have changed the face of the HIV epidemic in the United States. People living with HIV are aging, and have increased heart, lung, and blood diseases compared to people without HIV. This project will fill important gaps in our knowledge about risk factors for development and complications of these conditions in people living with HIV, leading to new prevention and treatment strategies.

CHS Events Follow-Up Study

CHS Events Follow-Up Study is a continuation and expansion of the work done through the Cardiac Health Study (CHS). CHS, a study of risk factors for coronary heart disease (CHD) and stroke, examined 5888 participants for data such as traditional risk factors and measures of sub-clinical CHD and conducted regular follow-ups. In addition to continuing to analyze the existing data, the investigators are following up with surviving participants twice a year to identify and classify potential cardiac and cerebrovascular events.

Other Activities

Exome Chip, New Endophenotypes & Functional Studies in CHARGE

A subgroup of the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) was one of four founding consortia of the International Genomics of Alzheimer Project (IGAP) and investigated Alzheimer’s Disease heritability. This project allows for a continuation of that work by using Illumina ExomeChip data to help explore the >65% of AD heritability that is still unexplained. Investigators use the ExomeChip data to find rare genetic variants related to incident clinical AD and AD endophenotypes. Additionally, investigators are studying gene-gene and gene-environment interactions related to AD.

Comparison of Safety Signaling Methods for Survival Outcomes to Control for Confounding the Mini-Sentinel Project

This project enhances the data analysis methods used in the FDA’s Sentinel Initiative to improve drug safety surveillance planning. In particular, we develop new methods for the analysis of survival data that control for confounding using propensity scores.

Arterial Structure and Function in Atrial Fibrillation

This project is designed to explore whether measures of arterial structure and function, such as carotid intima-media thickness (cIMT) and pulse pressure, may be used to help predict atrial fibrillation (AF) and its sequelae. AF is the most common sustained cardiac arrhythmia and its prevalence, particularly in the aging population, causes considerable morbidity, mortality and socioeconomic burden. Better risk prediction of AF and its sequelae would enable us to identify individuals who will benefit from preventative interventions, helping reduce the burden of AF in the elderly population.

Epidemiology of Venous Thrombosis and Pulmonary Embolism

This Longitudinal Investigation of Thromboembolism Etiology (LITE) is a project that aims to identify risk factors for deep thromboembolism and pulmonary embolism, and to better understand the etiology and possible prevention of VTE. Working with the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovardiovascular Health Study (CHS) cohorts, CHRU investigators are using biomarkers, fine-mapping and genetic association analysis to find associations with VTE.

A Multi-Ethnic Study of Gene-Lifestyle Interactions in Cardio Traits

This project allows investigators to use extraordinary access to multi-ethnic studies and cohorts that have phenotypes, relevant lifestyle data and dense genotype data on common as well as rare variants in an effort to explore how the environment modulates genetic effects in influencing cardiovascular disease and its risk factors. The project involves 25 cohorts with over 150,000 subjects, for whom investigators will study gene-lifestyle interactions, pleiotropy analysis and pathway analysis. This data may offer important clues for intervention and novel therapeutic approaches.

Rare Sequence Variation and Diabetes Quantitative Traits

Type 2 diabetes is a growing health problem worldwide. In this project, we use innovative approaches to identify new molecular targets for the prevention and care of people with diabetes. We propose to move type 2 diabetes genetics from common variant genome wide association studies to rare variant whole genome sequencing. In this project, we use whole genome sequence data from several thousand participants in the CHARGE Consortium, we annotate variants using ENCODE and other resources, and we confirm predicted allele-specific molecular function in vitro.