Redford B. Williams - US grants

The long range goal of this project is to define the role of psychosocial factors in determining phathogenesis and outcomes of coronary heart disease (CHD); and, ultimately, to apply such knowledge to the prevention, treatment and rehabilitation of CHD. During the next 3-year period primary efforts will focus on analysis of data already in hand on over 1500 patients who underwent coronary angiography at Duke and who will be followed indefinitely. Building on the work to date, three specific aims are proposed. 1) High scores on an MMPI "hostility"(Ho) scale correlate with coronary atherosclerosis (CAD) in our selected clinical sample, and they prospectively predict CHD events as well as total mortality in both a middle-aged and a young sample, each of which took the MMPI 25 years ago. We and one other group have now succeeded in factor analyzing the MMPI at the item level, and have both found similar reliable item clusters related to hostility which appear to have construct validity. We propose to evaluate these clusters as both correlates of CAD in our clinical sample and predictors of CHD and other health outcomes in the two prospective samples, as well as a new sample of 1000 naval submariners who took the MMPI 15 years ago when their mean age was 26. 2) Analysis of Functional Status Questionnaire data on over 1900 patients has enabled us to derive independent scales which appear to be reliable and valid measures of the following aspects of the quality of life: physical activity at work and elsewhere; sufficiency of financial resources; perceived adequacy of social support; and frequency of social contacts. We propose to use these scales both as baseline predictors and follow-up indices to evaluate the quality of life outcome in medically and surgically treated patients, and to see if just as with the angina outcome there are baseline physical and psychosocial predictors of the more broadly defined quality of life outcome. 3) Death and CHD events are now mounting in our sample since data collection began over 8 years ago. We propose to do further Cox model analyses to identify baseline psychosocial factors which predict CHD morbidity and mortality independently of potent physical predictors; also to see if angina relief over longer follow-ups and in patients on Ca++ blockers is predicted by psychosocial factors. Achievement of these of these aims will refine the definition of coronary prone behavior, increase knowledge regarding determinants of a wide variety of CHD outcomes and, ultimately; could lead to new knowledge which would improve approaches to the prevention, treatment and rehabilitation of CHD.

The objective of the proposed research is to identify and characterize patterns of physiologic and behavioral response which are reliably expressed together under specific conditions of organism-environmental interaction. Eventually, knowledge of such behavioral/physiologic linkages can be applied in identifying basic mechanisms whereby the role of behavioral factors in pathogenesis of cardiovascular disease is mediated. The central nervous system appears organized to produce patterns of responses, rather than isolated responses of single variables. One well-known example of such a pattern is that known as the "defense reaction", consisting of increased somatomotor activity and cardiac output, with shunting of blood away from skin and viscera to skeletal muscles. This pattern is elicited in circumstances requiring either emergency motor activity or mental work. Recent work leads to the hypothesis of another, qualitatively different pattern of behavioral/physiologic response under circumstances requiring the organism to engage in sensory intake behavior. Here, the physiologic response pattern appears to be one of decreased somatomotor activity and cardiac output, with an active vasoconstriction in skeletal muscle as well as skin and viscera. We shall test this hypothesis by comparing physiologic and neurohumoral response patterns in a large sample of young males under conditions of mental work versus conditions requiring sensory intake behavior. The reliability and generalizability of the sensory intake pattern will be tested, along with the influence of individual differences in cognitive style. Preliminary assessment of sensory intake and mental work/defense patterns in cardiovascular disease pathogenesis will include evaluation of the relation of coronary-prone (Type A) behavior pattern and presence of hypertension and coronary disease to patterns of behavioral/physiologic response under mental work and sensory intake conditions.

The broad objectives of the research to be done on this ADAMHA RSA are: 1) to identify psychological traits responsible for the increased coronary heart disease (CHD) risk among Type A persons; 2) to identify biological mechanisms mediating this increased CHD risk; and 3) to use the knowledge gained to devise effective prevention and treatment measures. Two general programs of research will be mounted to achieve these goals. Epidemiological studies will be done to refine a hostility/cynicism scale which appears to predict a broad range of adverse health outcomes; and to establish its construct validity. Along with measures of Type A, anger exprience and anger expression, a questionnaire containing hostility/cynicism items will be administered to healthy groups and to patients undergoing coronary angiography. If correlations with other measures suggest construct validity for the new cynicism scale and if it predicts CHD events and accounts for the relation of Type A to coronary atherosclerosis (CAD), the first objective will be achieved. A series of biobehavioral studies will be done comparing cardiovascular and neuroendocrine responses of Type A and B men to tasks requiring sensory intake versus mental work behavior. The generalizability of lab findings to real life will be evaluated by obtaining 24hr urine samples on these subjects and seeing if lab neuroendocrine responses predict urinary excretion levels. Statistical analyses will evaluate the effect of hostility/cynicism levels and aging on the observed responses, both in the lab and natural settings. Persistent hyperresponsivity among men with more severe CAD will be evaluated and if present would support pathogenic involvement of such hyperresponsivity. Behavioral paradigms which elicit the same neuroendocrine response patterns in the rat will be evaluated with the goal of showing that such response patterns are capable of potentiating atherogenesis in an animal model. The effects of beta-blockers and benzodiazipines on both humans' and rats' responses to the behavioral paradigms will be evaluated, both to learn more about mechanisms of the responses and to begin to devise intervention approaches. Collaboration in doing this research with established investigators in the relevant areas will contribute to the professional growth of the Principal Investigator. Successful completion of the proposed studies will result in substantial progress toward identifying the key psychological trait(s) predisposing to increased CHD risk among Type A persons, as well as the intervening biological mechanisms. Such knowledge will contribute to development of effective prevention and treatment approaches.

The long term objective of this program project continues to be to elucidate the role of biobehavioral factors in the etiology, pathogenesis and course of coronary heart disease (CHD). Our integrative theme has expanded from its primary focus on hostility to include a set of psychosocial, behavioral and biological characteristics that increase (SES). To pursue this theme, investigators with a variety of disciplinary backgrounds - psychiatry, medicine, psychology, pharmacology, pathology, biostatistics, epidemiology, molecular biology and neurobiology - will work to achieve three broad, programmatic objectives: 1) Evaluate the association between interrelated sets of psychosocial risk factors and behavioral and biological (including the cellular/molecular level) mediators of pathogenesis; 2) Identify environmental antecedents of the psychosocial/behavioral profile that increase pathogenesis; and 3) Evaluate in both humans and an animal model the possible role of reduced brain serotonergic function as a mediator of the clustering in certain individuals and low SES groups of psychosocial and biobehavioral mediators of pathogenesis. Project 1 will evaluate the association between psychosocial risk factors and biological mechanisms at both the "macro" and cellular levels that could be responsible for pathogenesis, with a special focus on low SES as an amplifer of psychosocial effects on biological mediators. Project 2 will evaluate the relation of brain serotonergic function to the set of psychosocial and biobehavioral risk mediators in Project 1's community sample of 400 persons stratified for SES, race and gender. Project 3 will use three ongoing large scale studies of Caucasian, American Indian, and African American boys and girls to evaluate the impact of harsh environments on the emergence of the adverse psychosocial/biobehavioral profile. Project 4 will use a rat model to evaluate the impact of early maternal deprivation on the development of biobehavioral characteristics analogous to those seen in humans with the adverse profile, and it will evaluate the role of brain serotonin in mediating this environmental impact. Resuults should enhance our understanding of the environmental and neurobiological bases of the clustering of psychsocial/biobehavioral risk factors in certain individuals and low SES groups, as well as the cellular and molecular processes whereby pathogenesis is mediated. Such increased understanding could lead to improved approaches to prevention and treatment of cardiovascular disease.

This renewal application for a post-doctoral training program that maintains and enhances a training environment to foster the development of the knowledge, skills, and the perspective essential to interdisciplinary research in the field of behavioral medicine. Support is requested for 8 trainees, half with basic research and half with clinical backgrounds, who would enter the program after receiving their degree or after 1-6 years of clinical training. A two-year program is proposed. The first year's activities are organized into four areas: 1) a biweekly Behavioral Medicine Research Seminar; 2) advanced training in biostatistics and epidemiology as need; 3) A Monthly Integrative Medicine journal club; and 4) acquisition of directed research in the preceptor's laboratory. The second year will be focused on the completion of the trainee's own research project. Research areas available to trainees include: the neurobiology of stress in animals; human stress psychophysiology; molecular biology of stress; epidemiological studies of psychosocial factors in disease; human and animal psychoimmunology; racial factors in stress and hypertension; developmental issues in behavioral medicine; and behavioral and pharmacologic approaches to the prevention, treatment, and rehabilitation of stress-related medical disorders. Training faculty conduct behavioral medicine research on the disorders of cancer, coronary heart, disease, depression, diabetes mellitus, pain syndromes, osteoarthritis, pain disorder, and depression. Disciplines included in the program are pathology, psychology (clinical, experimental, social, and biological), neurobiology, pharmacology, immunology, epidemiology, biostatistics, psychiatry, internal medicine, and cardiology. An interdisciplinary approach to behavioral medicine will be fostered by the example of senior faculty and specific encouragement of collaborative projects among trainees. The objective is the development of behavioral medicine researchers skilled in their own specialty but able to collaborate successfully with specialists in other fields on research questions of importance to behavioral medicine.

The long range goal of this research is to determine whether deficient vagal antagonism of sympathetic nervous system (SNS) actions on the heart contributes to increased CHD risk in hostile person's. Specific aims include the use of sophisticated electrophysiologic monitoring approaches to: 1) show greater sensitivity in nonhostile young men to T-wave attenuation effects of isoproterenol infusion following vagal blockade; 2) show that vagal enhancement reduces and shortens the T-wave attenuation effects of isoproterenol infusion more in hostile young men; 3) evaluate these effects of vagal blockage and enhancement in middle-aged men and in young and middle-aged women; and 4) relate the T-wave effects in these studies to other measures of vagal tone and other biobehavioral mechanisms of cornonary-prone behavior. Four studies will be done in normal young and middle-aged men and women selected as high and low on hostility, evaluating vagal tone measures and effects of isoproterenol infusion on EKG T-wave and ST response after pretreatment with saline, neostigmine, and atropine. Demonstration that hostility is associated with deficient vagal anatagonism of SNS effects on the heart, especially in middle-aged as compared to younger persons, would suggest that diminished vagal tone is one pathway whereby high hostility contributes to increased CHD risk. Clinical studies would then be indicated to determine whether weaker vagal tone predicts increased myocardial ischemia and/or poorer outcomes in CHD patients. Knowledge gained in this research program could help to develop more effective preventive, treatment, and rehabilitation approaches to coronary disease.

The long range goal of this research is to determine whether deficient vagal antagonism of sympathetic nervous system (SNS) actions on the heart contributes to increased CHD risk in hostile person's. Specific aims include the use of sophisticated electrophysiologic monitoring approaches to: 1) show greater sensitivity in nonhostile young men to T-wave attenuation effects of isoproterenol infusion following vagal blockade; 2) show that vagal enhancement reduces and shortens the T-wave attenuation effects of isoproterenol infusion more in hostile young men; 3) evaluate these effects of vagal blockage and enhancement in middle-aged men and in young and middle-aged women; and 4) relate the T-wave effects in these studies to other measures of vagal tone and other biobehavioral mechanisms of cornonary-prone behavior. Four studies will be done in normal young and middle-aged men and women selected as high and low on hostility, evaluating vagal tone measures and effects of isoproterenol infusion on EKG T-wave and ST response after pretreatment with saline, neostigmine, and atropine. Demonstration that hostility is associated with deficient vagal anatagonism of SNS effects on the heart, especially in middle-aged as compared to younger persons, would suggest that diminished vagal tone is one pathway whereby high hostility contributes to increased CHD risk. Clinical studies would then be indicated to determine whether weaker vagal tone predicts increased myocardial ischemia and/or poorer outcomes in CHD patients. Knowledge gained in this research program could help to develop more effective preventive, treatment, and rehabilitation approaches to coronary disease.

The long range goal of this research is to determine whether deficient vagal antagonism of sympathetic nervous system (SNS) actions on the heart contributes to increased CHD risk in hostile person's. Specific aims include the use of sophisticated electrophysiologic monitoring approaches to: 1) show greater sensitivity in nonhostile young men to T-wave attenuation effects of isoproterenol infusion following vagal blockade; 2) show that vagal enhancement reduces and shortens the T-wave attenuation effects of isoproterenol infusion more in hostile young men; 3) evaluate these effects of vagal blockage and enhancement in middle-aged men and in young and middle-aged women; and 4) relate the T-wave effects in these studies to other measures of vagal tone and other biobehavioral mechanisms of cornonary-prone behavior. Four studies will be done in normal young and middle-aged men and women selected as high and low on hostility, evaluating vagal tone measures and effects of isoproterenol infusion on EKG T-wave and ST response after pretreatment with saline, neostigmine, and atropine. Demonstration that hostility is associated with deficient vagal anatagonism of SNS effects on the heart, especially in middle-aged as compared to younger persons, would suggest that diminished vagal tone is one pathway whereby high hostility contributes to increased CHD risk. Clinical studies would then be indicated to determine whether weaker vagal tone predicts increased myocardial ischemia and/or poorer outcomes in CHD patients. Knowledge gained in this research program could help to develop more effective preventive, treatment, and rehabilitation approaches to coronary disease.

neuroregulation; health behavior; neurotransmitter metabolism; coronary disorder; serotonin; disease /disorder proneness /risk; socioeconomics; gender difference; clinical trials; brain metabolism; racial /ethnic difference; behavioral /social science research tag; clinical research; caucasian American; human subject; African American;

The long range objective of this project is to evaluate the role of central nervous system (CNS) serotonin function as a potential mediator of the clustering of health-damaging psychosocial and biobehavioral characteristics in the same individuals and low socioeconomic status (SES) groups. Specific Aims to achieve this goal are: 1) Use CSF 5-HIAA and behavioral and biological responses to serotonin enhancement and depletion to evaluate CNS serotonergic function in a community sample of normal young adults who are sampled to provide equal numbers with high vs low SES level male and female gender, and Black and White race. 2 Determine whether there is an association between lower CNS serotonergic function -- indexed by CSF 5HIAA -- and increased prevalence of the set of psychosocial and biobehavioral risk factors across individuals. 3. Determine whether the expected association between lower SES and increased prevalence of psychosocial and biobehavioral risk factors is weakened or abolished by adjustment for CNS serotonergic function. 4. Determine the effects of acute serotonin enhancement and depletion on biological and mood responses to the lab stressors used in Project 1 among subjects low in SES and CNS serotonin function. We shall recruit a community sample of 400 subjects, stratified as in Aim 1, who will be studied during a 2.5 day admission to our linical Research Center. During that time they will undergo a lumbar puncture to provide cerebrospinal fluid (CSF) for assay of CSF 5-hydroxyindole acetic acid (5HIAA) a reliable measure of FNS serotonin turnover. They will also be subjected to serotonin-depletion using the tryptophandepletion method and serotonin enhancement using the drug fenfluramine. We shall evaluate and compare the relationship of SES and CSF 5HIAA to the profile of psychosocial and biobehavioral risk factors, and the effects of serotonin depletion and enhancement on measures of mood, cardiovascular and neurodocrine function, as well as on responses of these functions to mental challenge. If we find that CSF 5HIAA relates more strongly to adverse psychosocial and biobehavioral profiles than SES, it will support our hypothesis that CNSserotonergic function is a mediator of the adverse profile per se, as well as of the impact of low SES on the profile. This hypothesis will be further supported if serotonin depletion and enhancement cause an increase and decrease, respectively, in mood and biological indicators of the adverse profile, with differential effects in subjects with high vs low CSF 5HIAA. Successful achievement of the long range goal of this project would lead to a major increase in our understanding of the neurobiological basis of the observed clustering of psychosocial, behavioral, and biological risk indicators in certain individuals and low SES groups. Such understanding has the real potential to identify effective preventive and treatment approaches to reduce the toll of cardiovascular disease in the U.S. each year.

The long term objective of this program project continues to be to elucidate the role of biobehavioral factors in the etiology, pathogenesis and course of coronary heart disease (CHD). Our integrative theme has expanded from its primary focus on hostility to include a set of psychosocial, behavioral and biological characteristics that increase (SES). To pursue this theme, investigators with a variety of disciplinary backgrounds - psychiatry, medicine, psychology, pharmacology, pathology, biostatistics, epidemiology, molecular biology and neurobiology - will work to achieve three broad, programmatic objectives: 1) Evaluate the association between interrelated sets of psychosocial risk factors and behavioral and biological (including the cellular/molecular level) mediators of pathogenesis; 2) Identify environmental antecedents of the psychosocial/behavioral profile that increase pathogenesis; and 3) Evaluate in both humans and an animal model the possible role of reduced brain serotonergic function as a mediator of the clustering in certain individuals and low SES groups of psychosocial and biobehavioral mediators of pathogenesis. Project 1 will evaluate the association between psychosocial risk factors and biological mechanisms at both the "macro" and cellular levels that could be responsible for pathogenesis, with a special focus on low SES as an amplifer of psychosocial effects on biological mediators. Project 2 will evaluate the relation of brain serotonergic function to the set of psychosocial and biobehavioral risk mediators in Project 1's community sample of 400 persons stratified for SES, race and gender. Project 3 will use three ongoing large scale studies of Caucasian, American Indian, and African American boys and girls to evaluate the impact of harsh environments on the emergence of the adverse psychosocial/biobehavioral profile. Project 4 will use a rat model to evaluate the impact of early maternal deprivation on the development of biobehavioral characteristics analogous to those seen in humans with the adverse profile, and it will evaluate the role of brain serotonin in mediating this environmental impact. Resuults should enhance our understanding of the environmental and neurobiological bases of the clustering of psychsocial/biobehavioral risk factors in certain individuals and low SES groups, as well as the cellular and molecular processes whereby pathogenesis is mediated. Such increased understanding could lead to improved approaches to prevention and treatment of cardiovascular disease.

The long-term objective of this research proposal is to elucidate underlying biological and behavioral mechanisms whereby stressful social and physical environments contribute to health disparities between socioeconomic and racial groups. To achieve this objective, the following Specific Aims are proposed: Aim 1 - To determine whether persons who are caregivers for a spouse with Alzheimer's Disease or other chronic dementia have a more adverse profile of behavioral and biological characteristics than matched controls without caregiving responsibilities. Aim 2 - To determine whether living in a stressful physical environment (based on neighborhood characteristics) leads to a more adverse profile of biobehavioral characteristics among caregivers than noncaregivers. Aim 3 - To determine whether the impact of stressful social and/or physical environments on health-damaging biobehavioral characteristics is moderated by the presence of a hostile personality type or genetic polymorphisms that affect CNS serotonin function. In secondary analyses, we shall also evaluate the moderating effect of other potential moderators - e.g., underlying CHD or other medical disorder, race, gender, social support, and socioeconomic status. We shall recruit a sample of 200 caregivers and 200 matched controls without caregiving responsibilities. We shall assess the impact of caregiver status on behavioral (negative affects and health practices) and biological (cardiovascular and neuroendocrine function at rest and during stress, metabolic syndrome) characteristics likely to underlie health disparities. We shall determine the impact of the physical neighborhood environment, both alone and interacting with caregiver status, upon the biobehavioral mechanisms. We shall also evaluate the moderating effects of serotonin-related genetic polymorphisms, hostile personality type and other medical/physical and social characteristics of the subjects upon the impact of caregiving and physical environments on biobehavioral mechanisms. In addition to increasing understanding of biobehavioral mechanisms responsible for health disparities, the findings could point to targets for specific interventions aimed at ameliorating these disparities.

The overall objective of this project is to determine the role of gene-environment interactions in the expression of psychosocial and biobehavioral risk factors for cardiovascular disease (CVD). We propose to identify variants in candidate genes and chromosomal loci that are associated with the endophenotypes of hostility, personality dimensions, other psychsocial risk factors, health behaviors, cardiovascular and neuroendocrine function at rest and in response to stress, indices of platelet activation and serotonin transporter function at rest and in response to stress, circulating inflammatory markers at rest and in response to stress, and the tendency of all these characteristics to cluster in the same individuals and low socioeconomic groups. We shall recruit 400 probands (half African American and half Caucasian, half men and half women, and half scoring in the top and half in the bottom 20% on a valid, measure of hostility that predicts CVD and has heritability estimates of 40-55%), at least one sibling for every proband, to make a total sample of 800-1200 subjects who will participate in the protocol of this project, and as many parents as are available who will be genotyped and complete only the paper and pencil tests. We shall genotype all probands, sibs, and parents for at least 41 candidate genes/loci for family-based association studies to identify polymorphisms of candidate genes/loci that influence, either directly or in interaction with environmental factors, or as a function of linkage disequilibrium with other sites or membership in haplotypes, the expression of hostility, personality dimensions related to hostility, other psychosocial risk factors, health behaviors, and cardiovascular, neuroendocrine, platelet, and inflammatory markers at rest and in response to a Mental Stress Protocol, as well as the tendency of these endophenotypes to cluster. As the first such large scale study to include adequate numbers of men and women and African Americans and Caucasians who are genotyped for candidate genes/loci that are examined for association with psychosocial and biobehavioral endophenotypes known to increase CVD risk and their tendencies to cluster, the proposed research has the potential to identify gene-environment interactions that increase CVD risk. Such knowledge could increase understanding of the contribution of gene-environment interactions to pathogenic mechanisms whereby psychosocial and biobehavioral risk factors increase CVD risk, thereby helping to identify highly susceptible persons who might be targets for primary prevention trials.

genetic susceptibility; psychological stressor; serotonin receptor; genetic polymorphism; serotonin; disease /disorder proneness /risk; clinical research; human subject;

DESCRIPTION (provided by applicant): For the previous 15 years of support on this program project grant, we have sought to identify psychosocial factors that increase cardiovascular disease risk and to understand the biobehavioral mechanisms whereby increased risk is mediated. During the current 5-year period of support, we have met our broad objectives to: 1) document the clustering of psychosocial and biobehavioral risk factors for CVD in persons of low socioeconomic status; 2) document the important influence of early environments on this clustering; and 3) document the role of brain serotonergic function as an important contributor to this clustering. We have also initiated a major new research initiative - identification of polymorphisms of serotonin-related genes as a new means of documenting the importance of serotonergic mechanisms in clustering of psychosocial and biobehavioral factors that increase CVD risk. Based on findings of extensive associations between polymorphisms of the serotonin transporter and monoamine oxidase A genes and phenotypes in every system we have studied during the current PPG, we propose now to undertake a large scale and ambitious study, involving up to 500 hostile probands and over 500 of their siblings, to identify genetic variants - using family-based association studies of candidate genes and loci - that influence the expression of hostility and the other psychosocial and biobehavioral enophenotypes that cluster with hostility in the same individuals and low SES groups. Project 1 will search for genetic variants that influence hostility, personality, and cardiovascular, neuroendocrine, and platelet functions, as well as circulating inflammatory markers at rest and in response to stress. Project 2 will search for genes that influence glucose metabolism and the metabolic syndrome. Project 3 will search for genes that influence ambulatory markers of stress in the real world. Five Cores will support the Projects. Representing a new collaboration between investigators in the Duke Behavioral Medicine Research Center and the Center for Human Genetics, the proposed research could identify genetic variants that interact with stressful environments to increase CVD risk via effects on healthdamaging psychosocial and biobehavioral endophenotypes - thereby increasing understanding of pathogenic mechanisms and raising the possibility of being able to identify highly susceptible persons who may be candidates for both secondary and primary prevention trials.

12-20 years old; 3-(2-Aminoethyl)-1H-indol-5-ol; 5-HT; 5-Hydroxytryptamine; 5HT; AOD use; Adolescence; Adolescent; Adolescent Youth; Age; Alcohol or Other Drugs use; Analysis, Data; Attention; Behavior; Biological; Candidate Disease Gene; Candidate Gene; Characteristics; DSM-IV; DSM4; Data; Data Analyses; Data Set; Dataset; Dependence; Development; Diagnostic and Statistical Manual of Mental Disorders, 4th edition; Diagnostic and Statistical Manual of Mental Disorders-IV; Disease Pathway; Drug usage; Enteramine; Environment; Ethnic Origin; Ethnicity; Ethnicity aspects; Gender; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic analyses; Genotype; Health; Hippophaine; Individual; Life; Life Cycle; Life Cycle Stages; Longitudinal Studies; Mediating; Outcome; Pathway interactions; Pattern; Polymorphism (Genetics); Polymorphism, Genetic; Polymorphism, Single Base; Race; Racial Group; Risk; Risk-Taking; SNP; SNP Map; SNPs; SUBGP; Sampling; Serotonin; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Social Behavior; Stocks, Racial; Subgroup; Substance of Abuse; System; System, LOINC Axis 4; Targetings, Gene; Testing; Time; adolescence (12-20); anti social; antisocial; dopamine system; drug use; environment effect on gene; environmental stressor; externalizing behavior; gene environment interaction; genetic analysis; high risk sex activity; high risk sex behavior; high risk sexual activity; high risk sexual behavior; juvenile; juvenile human; life course; long-term study; pathway; polymorphism; psychologic; psychological; response; risky sexual behavior; social; sociobehavior; sociobehavioral; substance use; substances of abuse; teenage

The overarching objective of this Project is to identify genetic variants that are associated, both as main effects and via interactions with exposure to environmental stressors, with incident cardiovascular events or coronary artery disease (CAD). To accomplish this goal, we will evaluate genes found associated in Projects 1 and 2 with CVD endophenotypes or in Project 3 with hypertension or type II diabetes (T2D), for associations with incident cardiovascular events and angiographically documented CAD in the CATHGEN sample of approximately 10,000 patients who have undergone cardiac catheterization at Duke since 2001. CATHGEN is a unique resource of biological samples collected at time of cardiac catheterization combined with a carefully adjudicated clinical database comprising angiographically-defined extent and anatomical distribution of coronary artery disease, extensive clinical data on CHD risk factors, and annual follow-up for evaluation of incident cardiovascular events. The CATHGEN investigators, under non-overlapping support from their NHLBI grant, will be evaluating a broad range of genes that are biologically plausible contributors to CHD pathogenesis and/or course or have been reported to be associated with CHD for associations with CAD and clinical events. Therefore, another aim of this Project, will be to collaborate with Projects 1, 2 and 3 to determine whether any genetic variants we fmd associated with CAD or clinical events in the CATHGEN sample are also associated with CVD endophenotypes, hypertension and/or T2D in their samples. As with Project 3, this Project provides the opportunity to take the critical step of translating gene associations with CVD endophenotypes into documented impact on disease endpoints.

Recent advances in genome sciences have resulted in a vast expansion of the resources and tools available to identify the major genetic determinants of complex traits including metabolic and cardiovascular disorders. However, dissecting the genetic basis of these traits requires not only technological advances, but access to well-characterized study populations, informatics infrastructure, appropriate, integrated statistical methodologies and expertise in the biology and epidemiology of these traits. We have designed Core B (the Genetics, Biostatistics and Bioinformatics Core) to support the three projects in the PPG through the following Specific Aims: 1.) Establish a clearinghouse of published single locus and GWAS results and open access genetic datasets in support of discovery of candidate genes and validation of specific hypotheses generated in our three projects;2.) Conduct analyses of open-access GWAS datasets to identify candidate genes to feed into our projects;3.) Coordinate analysis of candidate genes and provide genotyping and statistical analysis support as needed across participating projects including the following: selection of specific SNPs to genotype;facilitiating interactions with the Genotyping Core;providing expertise and facilitites for statistical analysis of not only genetic data, but complex psychosocial data, including the testing of the components of the theoretical model that guides this PPG;and finally, coordinating analyses and sharing of results across projects;and 4.) Identify and establish collaborations with additional study pouplations for further replication of our findings, obtain DNA/data and support genotyping and analysis of these projects as needed.

DESCRIPTION (provided by applicant): The Society of Behavioral Medicine is the organizing entity for the 11th International Congress of Behavioral Medicine (ICBM2010) to be held in Washington, DC, August 4-7, 2010 in collaboration with the International Society of Behavioral Medicine. The theme of the Congress, "Translational Behavioral Research: A Global Challenge," recognizes the importance of worldwide collaboration. In order to promote the growth and development of the most promising scientists, the primary use of the funds being sought through this application will be to support the participation of approximately 20 young investigators from developing countries and from the US, and 10 established investigators from developing countries in this exceptional, multidisciplinary and multi-national scientific forum. Programmatically, ICBM2010 will address numerous aspects of the National Cancer Institute's extensive behavioral research objectives. These include developing a better understanding of the root causes of cancer that include lifestyle factors and environmental exposures, cancer prevention and control, reducing the magnitude of health disparities and, identifying modifiable risk factors. The ICBM2010 program is also relevant to many other NIH Institutes and Centers (ICs) whose missions are advanced through the basic behavioral sciences, behavioral epidemiology, preventive interventions, and translation research. These include NCCAM, OBSSR, NHGRI, NIA, NIDHD, NINDS, NHLBI, NIDDK, NIAID, NIDA, NIAAA, NIMH and others. The 11th International Congress of Behavioral Medicine is the premier international forum for advancing our understanding of the challenges underlying the translation of clinical and public health research evidence to practice. In the words of the Board on Global Health (2009): "Working with partners in other countries and building on previous commitments, [we have] the opportunity to demonstrate global leadership by fulfilling [our] responsibility to save lives and improve the quality of life for millions around the world." Through its comprehensive program of research presentations by speakers from six continents and keynote and master lectures by internationally recognized authorities, ICBM2010 is an important step toward this goal. In pursuit of this mission, the purpose of this application is to support participation in ICBM2010 of the best and brightest investigators by easing the economic burdens that might otherwise prevent their participation.

The overarching objective of this Project is to identify genetic variants and environmental factors that act, whether interactively or Independently (main effects), to influence the expression of a wide range of psychosocial, behavioral and biological characteristics [CVD and Type 2 Diabetes (T2D) endophenotypes] that increase the risk of developing CVD and T2D among healthy persons as well as increase the risk of adverse clinical events in persons in whom CVD is already manifest. To achieve this objective we shall use three samples - PPG-1 (N=165), Caregiver (170 caregivers of a relative with Alzheimer's Disease, 170 controls) and PPG-2 (644 from 400 families); with a total N of 1000+/- - in which we have extensive data re a broad range of T2D and CVD endophenotypes to identify promising genetic variants (using both candidate genes and GWAS-derived SNPs) that are associated with these predisease endophenotypes. A major thrust of our work on this Project will be to increase our confidence in the reality of these gene endophenotype associations by replicating them, both within the three samples used by Project 1 and in the large healthy and clinical CAD samples being studied in Projects 2 and 3. A third aim will be to work closely with Projects 2 and 3 to complete the translational process, by showing that the genetic variants found associated in Project 1 with T2D and CVD endophenotypes are also associated in those Projects' samples with both the prevalence and incidence of CVD and T2D and clinical course.

The overarching objective of this Project is to identify genetic variants and environmental factors that act, whether interactively or Independently (main effects), to influence the expression of a wide range of psychosocial, behavioral and biological characteristics [CVD and Type 2 Diabetes (T2D) endophenotypes] that increase the risk of developing CVD and T2D among healthy persons as well as increase the risk of adverse clinical events in persons in whom CVD is already manifest. To achieve this objective we shall use use three samples - PPG-1 (N=165), Caregiver (170 caregivers of a relative with Alzheimer's Disease, 170 controls) and PPG-2 (644 from 400 families); with a total N of 1000+/- - in which we have extensive data re a broad range of T2D and CVD endophenotypes to identify promising genetic variants (using both candidate genes and GWAS-derived SNPs) that are associated with these predisease endophenotypes. A major thrust of our work on this Project will be to increase our confidence in the reality of these geneendophenotype associations by replicating them, both within the three samples used by Project 1 and in the large healthy and clinical CAD samples being studied in Projects 2 and 3. A third aim will be to work closely with Projects 2 and 3 to complete the tranlational process, by showing that the genetic variants found associated in Project 1 with T2D and CVD endophenotypes are also associated in those Projects' samples with both the prevalence and incidence of CVD and T2D and clinical course.

?DESCRIPTION (provided by applicant): Our program, developed over 25 years of NHLBI support, has identified and continues to identify gene variants that interact with psychosocial stressors to influence, via central nervous system and peripheral mechanisms, expression of behavioral and physiological endophenotypes in pathways to cardiometabolic disease and adverse clinical course. During the renewal period, using current PPG samples (N=26,010) and public-access samples (N=51,651), Project 1 will continue this work by using traditional and novel high throughput bioinformatics approaches to identify and validate new and previously identified gene variants and gene-by stress interactions that influence disease pathways, adapting novel statistical approaches to evaluate effects on multiple cardiometabolic endophenotypes in the pathways to disease outcomes as a system, including multiple genes and mediating biological pathways. We will evaluate race as a moderator of these GxStr effects on disease pathways and outcomes. We will also use multiple, multimethod discovery techniques to converge on additional variants in the genetic architecture of GxStr. Project 1 will pass previously and newly identified gene variants associated, both directly and via interaction with stress, with cardiometabolic endophenotypes to Project 2 to test for effects on endophenotypes in pathways to type 2 diabetes, to Project 3 to test for effects on epigenetic, transcriptomic and metabolomics pathways that mediate effects on endophenotypes and disease endpoints, and to Project 4 to test for effects on response of endophenotypes to behavioral and drug interventions. Project 3 will also evaluate effects of gene variants associated with cardiometabolic responses to behavioral and pharmacologic interventions in Project 4 for effects on molecular epigenetic, transcriptomics and metabolomics mechanisms. Project 3 will use whole exome sequencing and who genome methylation to identify genetic and epigenetic variants associated with mental stress-induced myocardial ischemia and Takasubo's cardiomyopathy. Project 4 will also test agonists and antagonists of the 5HTR2C receptor to see if they increase and decrease, respectively, the enhanced cortisol response to mental stress we have found associated with the rs6318 Ser23C allele. Successful completion of the proposed research in Projects 1-4 will increase our understanding of GxStr interactions on the multiple pathways that influence the development and course of cardiometabolic disease - knowledge that will be critical for the ultimate development of effective preventive and treatment interventions.

This resource has been designed to ensure smooth functioning and to accomplish the goals of this program project. The Administrative Core provides a formal structure for oversight, planning, and operational matters of the program projects activities and coordinator of shared resources. This structure has responsibility for scientific oversight, monitoring and quality control and operational issues and budgetary oversight. This structure also interacts as the interface with all participating organizational entities with Duke. The roles and responsibilities are defined. The committees that will help including the scientific and external advisory committees are structured and the mechanics of their operation are specified.

Recent advances in genome sciences have resulted in a vast expansion of the resources and tools available to identify the major genetic determinants of complex traits including metabolic and cardiovascular disorders. However, dissecting the genetic basis of these traits requires not only technological advances, but access to well-characterized study populations, informatics infrastructure, appropriate, integrated statistical methodologies and expertise in the biology and epidemiology of these traits. We have designed Core B (the Genetics, Biostatistics and Bioinformatics Core) to support the three projects in the PPG through the following Specific Aims: 1.) Establish a clearinghouse of published single locus and GWAS results and open access genetic datasets in support of discovery of candidate genes and validation of specific hypotheses generated in our three projects; 2.) Conduct analyses of open-access GWAS datasets to identify candidate genes to feed into our projects; 3.) Coordinate analysis of candidate genes and provide genotyping and statistical analysis support as needed across participating projects including the following: selection of specific SNPs to genotype; facilitiating interactions with the Genotyping Core; providing expertise and facilitites for statistical analysis of not only genetic data, but complex psychosocial data, including the testing of the components of the theoretical model that guides this PPG; and finally, coordinating analyses and sharing of results across projects; and 4.) Identify and establish collaborations with additional study pouplations for further replication of our findings, obtain DNA/data and support genotyping and analysis of these projects as needed.

PROJECT 1 ? Gene x Stress interactions' impacts on pathways to cardiometabolic disease PROJECT SUMMARY Our program, developed over 25 years of NHLBI support, has identified and continues to identify gene variants that interact with psychosocial stress to influence, via central nervous system and peripheral mechanisms, expression of behavioral and physiological endophenotypes in pathways to cardiometabolic disease and adverse clinical course. During the renewal period Project 1 will extend and substantially refine this work. Among the major challenges in studying gene by stress interactions are the need for a large number of individual observations in order to yield adequate statistical power and precision, and the relative absence of explicit measures of stress in prior studies. Project 1 addresses the first challenge by, in collaboration with the Biostatistics and Bioinformatics Core, harmonizing a number of large existing datasets, which will in turn be used to validate previous and newly discovered findings (Aim 1), and to embed those findings in the broader context of race (African Americans and Caucasians) (Aim 2) and potential mediating mechanisms that are thought to link variants to cardiometabolic disease. Project 1 overcomes the absence of explicit measures of stress by constructing a synthetic index of stress using bioinformatics techniques, which have proven successful in our preliminary work. We also will continue our discovery approach using high-throughput computational bioinformatics approaches, and gene x stress GWAS will be used in large publically accessible databases (e.g., MESA, FHS, CARDIA. Jackson Heart Study) to identify new gene variants associated with cardiometabolic endophenotypes (Aim 3). These newly discovered variants will be validated in new data derived from the harmonization. Project 1 also will pass previously and newly identified gene variants associated, both directly and via interaction with stress, with cardiometabolic endophenotypes to Project 2 (to test for effects on endophenotypes in pathways to type 2 diabetes), Project 3 (to test for effects on epigenetic, transcriptomic and metabolomics mechanism that mediate effects on endophenotypes and disease endpoints), and Project 4 (to test for effects on response of endophenotypes to behavioral and drug interventions). Successful completion of these aims will increase our understanding of gene x stress interactions that link stress to the development and course of cardiometabolic disease, knowledge that will be critical for the ultimate development of effective preventive and treatment interventions.