Genetic Epidemiology is the study of genetic factors that independently or in combination with environmental factors influences the risk of disease. Genetic epidemiology uses a variety of study designs including family and population approaches to investigate disease risk. Departmental faculty use the methods of genetic epidemiology to investigate genetic susceptibility and gene-environment interaction in relation to cancer, cardiovascular disease, reproductive and pediatric disease, and other health conditions.
Dr. Christy Avery: Genetic variants associated with complex diseases; Adverse drug reactions; Genome-wide association studies.
Dr. Jeannette Bensen: Breast cancer susceptibility; Racial differences in prostate cancer; Birth defects etiology and prevention; Cancer survivors.
Dr. Kimon Divaris: Genetics of oral and dental traits; dental caries; periodontal disease; gene-environment interactions; genome-wide association studies; gene-centric and pathway analyses; trans-ethnic studies; health disparities; qualitative studies
Dr. Nora Franceschini: Genetics of chronic kidney disease and blood pressure in diverse populations.
Dr. Misa Graff: Genetic variants associated with complex diseases.
Dr. Kari North: Genetic epidemiology of complex traits and obesity; research that takes place at the intersection of human genetics, epidemiology, statistical techniques and interdisciplinary translational research.
Dr. Til Stürmer: Adverse drug reactions; Genome-wide association studies.
Dr. Eric Whitzel: Adverse drug reactions; Genome-wide association studies.
Dr.Kristin Young: Genetic variants associated with complex diseases.
Affiliated genetic epidemiology faculty are involved in a number of diverse research projects, a number of which are listed below. Other genetic and molecular epidemiology projects can be found in faculty and program research profiles.Genetic Research Projects
The main goal of this project is to establish in UNC-SPH an innovative analytical laboratory that will support development of new biomarkers of susceptibility to adverse effects of chronic exposures to iAs. The project includes two pilot studies that will examine As species in cells collected from humans exposed to As. (Ethan Lange)
A population-based case-control study of breast cancer in African Americans and whites in North Carolina. Primary goal is to investigate a polygenic model for breast cancer susceptibility; gene-environment interaction.
This proposal aims to identify gene variants in chromosome 17 associated with blood pressure variation and susceptibility to hypertension, by following-up persuasive linkage findings of blood pressure in American Indian participants of the Strong Heart Family. Study (Nora Franceschini, Kari North)
The objective of this study is to investigate the mechanistic link between dietary fiber, gut microflora, butyrate, and epigenetic modifications which result in gene expression changes that alter cancer susceptibility. (Ethan Lange)
This project examines relationship between diabetes mellitus and exposure to inorganic arsenic from drinking water. (Ethan Lange)
The purpose of this grant is to investigate for genetic modifiers that influence severity of cystic fibrosis (CF) among CF patients carrying mutations in the CF gene. (Ethan Lange)
Genes Environment and Melanoma Study website.
In this study, we will characterize the genetic, epigenetic, and environmental progression of obesity and CMD across the lifecourse. We will leverage longitudinal assessments of body mass and adiposity, novel biomarkers, health, neuropsychology and environmental factors from infancy to young adulthood on over 1,100 study participants, from a unique Chilean study that presents a rare opportunity to assess how and when early genetic, epigenetic, environmental, and psychosocial risks for obesity and CMD begin. We will generate high throughput genotype data on the Illumina Global power chip designed to characterize ancestrally diverse populations to create a valuable resource for future studies. In the long term, the genetic interrogation of obesity and its environmental antecedents in early adulthood will advance science in developmental human pathophysiology and will contribute to the understanding of multifaceted causes of obesity that affect vulnerable populations in the US and around the globe. (Kari North)
The overall goal of this proposal is to investigate the genetic epidemiology of non-alcoholic fatty liver disease, abdominal fat, and the relationship of these phenotypes to other components of metabolic syndrome. (Kari North)
Comprehensive search for susceptibility genes. (Robert Millikan)
The aim of this study is to detect, map, and identify polymorphic genes that influence variation in CVD related phenotypes in participants of the Atherosclerosis Risk in Communities Study. (Kari North)
Purpose:This project proposes to investigate the genetic underpinning of early childhood caries (ECC), which is the most common chronic childhood disease and an important public health problem. The proposed study will address an important gap in our understanding of ECC’s genetic determinants. This study’s results have the potential to identify important genes and pathways as candidates for future mechanistic research, and can inform risk stratification and disease prediction for targeting high-risk children with early, intensive caries-preventive protocols. Participants: We propose to conduct clinical and genotype characterization in a multiracial/ethnic sample of approximately 6,000 3-5 year-old children enrolled in a federal preschool program, Head Start (HS)/Early Head Start (EHS) in North Carolina. We will conduct a pilot study to test and refine our proposed procedures and gather preliminary pilot data in local HS/EHS programs.
Procedures (methods):We will conduct dental examinations to diagnose ECC prevalence and severity among participating children using visual diagnostic criteria. We will collect saliva samples that will be used for DNA extraction and subsequent genotyping to enable a genome-wide association study (GWAS) of ECC. As part of our clinical activities we will additionally collect microbial plaque samples from children’s teeth to enable microbial analyses of ECC-related bacteria. Further, caregivers/parents will complete a short survey of ECC-related behaviors and practices (i.e., frequency of tooth brushing) and will be asked to provide a sample of their potable water source to enable analyses of fluoride content, a known chemoprotective against caries. (Kimon Divaris, Kari North)
This four-year prospective follow-up study of North Carolina PCaP participants aims to investigate the role of health insurance and access to care in racial differences in prostate cancer treatment and quality of life. (Jeannette Bensen)
Hispanic Community Health Study website.
The objectives of this study are to identify the prevalence of and risk factors for diseases, disorders, and conditions in Hispanic populations and to determine the role of acculturation and disparities in the prevalence and development of these conditions. (Kari North)
The objective of this study is to identify loci and genes that influence blood pressure variation across multiple population (Strong Heart Family Study, HyperGEN, ARIC) (Nora Franceschini)
The major goals of this project are to provide scientific leadership and expertise for specific cross-program objectives and to provide program coordination for administrative, logistical, and outreach activities. The proposed NHGRI Genome Sequencing Program Coordinating Center (GSPCC) will provide centralized and collaborative program coordination and scientific leadership to the Centers for Complex Disease Genomics (CCDG) and the Centers for Mendelian Genomics (CMG). The GSPCC will lead an analysis to evaluate when a common disease variant discovery study is effectively complete, develop specifications for a set of common controls for common disease rare variant studies, produce allele frequency data for the CMG program, and provide input into other cross-program activities as needed. The GSPCC will also coordinate logistics, communication, and outreach activities including scheduling and running meetings and teleconferences, hosting websites for data distribution and dissemination of project information to the public, and organizing other efforts as needed by the GSP. Coordination of the program will be done in a spirit of collaboration using creative, flexible, impartial approaches. Throughout the project the GSPCC will work with the funded GSP centers, the steering committee and the NHGRI to help facilitate a comprehensive and successful program of research to meet the goals of the GSP in promoting discovery of disease-related variants and identification of their potential causal roles. Our collaborative CC team is ideally staffed to meet the needs of the GSPCC. (Kari North)
This project conducts birth defects ascertainment in North Carolina, in collaboration with a national birth defects case-control study. The primary goal is to initiate studies of birth defects etiology and prevention in a cohort of case and control parent-child trios with a focus on investigating environmental exposures and genetic factors contributing to birth defects susceptibility. (Jeannette Bensen)
Prescription drug use has surged over the past five decades, being accompanied by an increased burden of adverse drug reactions (ADRs) that cause approximately 100,000 deaths and 2.2 million serious events in the U.S. annually. One promising research area that may improve ADR prediction is pharmacogenomics, a field in which gene-environment interactions have been replicated. Electrocardiographic (ECG) measures are excellent candidates for pharmacogenomic inquiry, as they are heritable, reliably measured, heterogeneous among populations exposed to drugs in the same class, and associated with a spectrum of cardiovascular diseases. QT interval (QT) prolongation, for example, is the most common cause of the withdrawal or restricted marketing of pharmaceuticals. Several studies have evaluated the pharmacogenomics of ECG traits including QT, although primarily in European (EU) descent populations. Expansion of pharmacogenomic research to include other race/ethnicities is warranted in view of US Food and Drug Administration-approved genotype-based dosing recommendations based primarily on EU populations despite evidence of influential race-specific variants. A parallel need is the increased representation of women, as they may harbor electrocardiographic and pharmacologic arrhythmia predisposition. We respond to these research gaps by examining genetic variants modifying the association between selected drugs/drug classes and ECG measures of ventricular and atrioventricular conduction in 32,851 Hispanic/Latino, African American, and EU participants from two large and well-characterized studies. Our results will be merged with the Cohorts for Heart and Aging Research in Genomic Epidemiology pharmacogenomics working group using trans-ethnic meta-analytic methods, yielding a combined population of 82,179 participants, with replication in an equally-sized multi-ethnic cohort. Fine-mapping that incorporates functional data will help narrow intervals surrounding significant loci and prioritize variants for future follow-up. This innovative study represents a unique opportunity to advance pharmacogenomic understanding of ventricular and atrioventricular conduction in global populations. Public health significance stems from the potential to develop tests that have favorable benefit-harm profiles, aid physicians in the selection of drug therapies or modification of dosing regimens, and reduce ADR-related morbidity and mortality. (Christy Avery, Til Stürmer, Eric Whitsel)
Genetic Epidemiology of Causal Variants Across the Life Course Phase II (CALiCo II) is a consortium of population based studies that have entered a partnership to provide optimal opportunities to investigate the association of genetic variants associated with complex diseases in ancestrally diverse populations. The first phase of CALiCo, CALiCo I, assessed the importance of common variants in diverse U.S. populations, public health-relevant contexts, and epochs in the natural history of chronic disease. CALiCo II will expand on these studies to assess low frequency [1-5% minor allele frequency (MAF)] and rare (0.1-1% MAF) coding and/or potentially functional genomic variants. The consortium comprises the Atherosclerosis Risk in Communities (ARIC) Study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the Hispanic Community Health Study (HCHS/SOL), the Strong Heart Study (SHS) and the Strong Heart Family Study (SHFS); and a Central Genotyping Core Laboratory located at the Human Genetics Center, University of Texas Health Sciences Center at Houston. These population-based studies have considerable breadth of phenotype characterization and population sizes to permit informative assessments of a wide range of variants, traits and public health contexts, with power sufficient to identify associations and interactions. This consortium brings several of the most informative studies extant and its core genotyping laboratory to a collaboration with other studies funded by this RFA, contributing well characterized cohorts under long term follow up, which include three main ethnic and racial groups in the U.S. (African Americans, Hispanics/Latinos, American Indians), and the ability to extend the characterization of genes and their associated traits and illnesses across the life course. In collaboration with Population Architecture Using Genomics in Epidemiology (PAGE) studies, CALiCo II will explore the associations of genetic variation with a broad range of phenotypes, including conditions that disproportionately burdens U.S. ethnic and racial minorities. (Kari North, Christy Avery, Misa Graff, Kristin Young)
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. Pharmacogenetic studies have usually relied on candidate-gene approaches; yet clinical applications with demonstrated health benefits remain few or far off. Recently, genome-wide association studies (GWAS) have discovered a large number of common genetic loci associated with complex disorders. GWAS methods to identify novel variants and pathways that affect drug response can complement the candidate-gene approaches. The setting is the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, formed to facilitate GWAS meta-analyses among multiple large population-based prospective cohort studies, including Age, Gene/ Environment Susceptibility Study, Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and the Rotterdam Study. Health ABC Study, the Multi-Ethnic Study of Atherosclerosis, the Coronary Artery Risk Development in Young Adults, and the Jackson Heart Study have joined the effort. The CHARGE data- sharing model has accelerated the discovery of novel genetic loci for complex diseases. With genome-wide data on more than 57,000 participants (22.4% African Americans), the proposed project will use GWAS methods to identify genetic loci that modify the effects of selected drugs on a variety of outcomes with a focus on unintended adverse drug effects. In this revised application, the primary aim involves the outcome of myocardial repolarization as assessed by the ECG QTc interval; and the four primary exposures of interest are: (1) use of high-torsades-risk QT-prolonging drugs (selected antiarrhythmics, antihistamines, antibiotics, and antidepressants); (2) sulfonylurea anti-diabetic agents; (3) thiazide diuretics, and (4) tri-cyclic and tetra- cyclic anti-depressants. In addition to this primary effort related to QTc, we plan to evaluate other potential drug-gene interactions such as the use of diuretics with serum potassium levels, the use of anti-depressants and diuretics with the ECG QRS interval, the use of beta-blockers and calcium antagonists and the PR interval, the use of aspirin with cardiovascular events (“aspirin failure” among aspirin users), and use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics with renal function. Public-health relevance: This broad-based discovery effort is likely to illuminate novel biologic mechanisms, affect how some drugs are prescribed, and identify novel targets for new therapies. (Christy Avery, Til Stürmer, Eric Whitsel)
The ICPCG Study website.
This is a collaborative study of prostate cancer genetics. (Ethan Lange)
To determine if genetic variations in apoptosis-related genes influence individuals’ apoptosis capacity and susceptibility to prostate cancer and other types of cancer. (Ethan Lange)
The major goals of this Consortium (PCaP) are to identify factors (including health care, diet, genetic, tumor biology) that influence the health disparity observed in prostate cancer mortality between African Americans and European Americans as well as to create an invaluable resource of clinical and epidemiologic data and biologic specimens that will be available for future studies. (Jeannette Bensen)
Strong Heart Family Study website.
The goal of this study is to detect, map, and identify polymorphic genes that influence variation in risk factors for cardiovascular disease and other related disorders that are major health problems in American Indians. (Nora Franceschini, Kari North)
Purpose: To address why among a cohort of indigenous Tsimane Amerindians in lowland Bolivia, do not develop heart disease as they age in the same ways as people in the developed world and why diabetes risk remains low throughout adulthood despite high levels of inflammation due to multiple infectious processes. Participants: 1000 Tsimane Amerindians who have been followed for 13 years Procedures (methods): To evaluate the influence of genetics on cardiovascular disease (CVD), and diabetes risk factors by analyzing stored biological samples of individuals over 40 years of age collected over the past decade who have contributed both longitudinal data on risk factors and (CVD), diabetes and immunological outcomes. (Kari North)
UNC Health Registry website.
A multi-component initiative to facilitate study of factors that affect the growing population of cancer survivors, known as the UNC Health Registry and Cancer Survivorship Cohort. This study will integrate, through a comprehensive database, clinical, epidemiological and interview data with repositories of biologic specimens and tumor tissue to provide a unique and extraordinarily rich cancer research resource. (Jeannette Bensen)
Women’s’ Health Initiative website.
The goal of this project is to identify putative variants for high-priority heart, lung, and blood phenotypes among post-menopausal minority women. (Kari North)
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