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Genetic Epidemiology

 
OPERATIONAL OBJECTIVES 

1. Develop a population-based genetic epidemiology resource for the study of common complex diseases in populations of the African Diaspora. 

Research Activity 

In the short term, the genetic epidemiology unit is developing a population-based resource for the NHGC at Howard to enhance the ability of center’s investigators to compete for external funds. This resource will include 600 multi-generational pedigrees (300 African Americans and 300 West Africans) with at least 5 persons per families. 

In the long term we will develop an international population repository of 1,500 multi-generational pedigrees of African origin populations with study sites in West Africa (Ghana and Nigeria; n=500 families), the Caribbean (Jamaica and Barbados; n=500 families) and the US (Washington, DC and Maryland; n=500 families) for a minimum sample size of 7,500 individuals.

To this end the Genetic Epidemiology unit has received initial funding to develop a population-based resource of 600 multi-generational African American (n=300 families and 1,500 persons) and West African (n=300 families and 1,500 persons) pedigrees to study the genetic epidemiology of diabetes, hypertension and obesity. The African Americans families will be enrolled from Washington, DC and Maryland communities. The West African families will be enrolled from Nigeria and Ghana. The manual of operation is complete and fieldwork is scheduled to start in the US in December of this year. In addition, we are in the process of securing funding to expand the study to the black Caribbean nations of Jamaica and Barbados.

Genetic diversity of African people 

An obvious benefit of the human Genome project is bound to be a better understanding of human evolutionary history. By employing recent molecular tools we can now study polymorphic markers (SNPs and STRs) on different chromosomes to understand the degree of similarity or divergence between African populations; a process that will have profound implication for blacks in the Western Hemisphere whose ancestors are the survivals of the forced migration out of the west and southwest coast of Africa.  Different groups have attempted to study these issues with varying success partly due to poorly developed hypotheses and the inherent biases ever present in the quest to understanding the origin of human civilization.  Proposed population-based resources will undoubtedly facilitate the full participation of investigators at the genome center at Howard University. A major goal of this genome center is to lead the discussion on genetic variation in populations of the African Diaspora.  

2.   Develop a major focus in the ethical issues related to the process of obtaining informed consent in genetic epidemiology studies at the national and international levels. 

To this end Dr. Rotimi is a Co-PI on a new initiative (an RO1 grant) titled “Informed Consent and Concepts of Race in Genetic Research” with Dr. Patricia Marshall as the Principal Investigator. This study hopes to advance our understanding of the ethical dimensions of genetic research in diverse populations. The process of obtaining informed consent provides the focus for ethical exchange between investigators and study participants. This study will take advantage of this social interaction to explore ethical issues associated with the implementation of collaborative international genetic research. In addition, broad issues of society will be addressed by examining how genetic identity and race are conceptualized in both the lay and professional communities. 

Dr. Rotimi’s participation in several national and international conferences addressing ethical issues in biomedical research is a demonstration of his commitment to this important area of research and community inclusion. He was a member of an international panel in a recently completed conference titled “First Community Consultation on the Responsible Collection and Use of Samples for Genetic Research” conducted by the Fogarty International Center. 

3.   Foster collaboration between the NHGC at Howard University and investigators in other minority institutions.

Commitment to this objective is evident in recent collaborations with Jackson Heart Study (JHS), Jackson, Mississippi and Morehouse School of Medicine, Atlanta, Georgia.  The Genetic Epidemiology unit is actively involved in the development of the research protocol for the family study component of the JHS. This component of the JHS is designed to detect genes influencing risk factors for a variety of heart, lung and blood disorders.  To this end, family enrollment is based on a random ascertainment strategy.  The Family study is nested within the JHS population-based sample, such that each participant eligible to participate in the JH cohort study is a potential proband (initial family contact) for the family study.  This will ensure that results obtained from the Family Study are generalizable to the greater JHS community. 

Another major objective of the NHGC at Howard University and the JHS collaboration is to increase minority participation in the national human genome project. To this end, Howard University investigators will conduct several training section in genetic epidemiology and ethical issues in biomedical research in Jackson, MS. Participants will include faculty members, graduate and undergraduate students in Jackson State University, Tougaloo College and the University of Mississippi Medical Center.  In addition, JHS investigators and students will have the opportunity to visit Howard University.   

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4.  Train minority investigators and Students at Howard University. 

An important reason underlying Dr. Rotimi’s move from Loyola University in Chicago is to increase the number of minority investigators participating in genetic epidemiology studies. The long-term goal is to maintain on staff at, all times, at least two post-doctoral fellows who will be interested in developing career in genetic epidemiology common complex diseases. To this end, the genetic epidemiology unit current has to fellows (Drs. Olufemi Adegoke and Gary Ellison) who are pursuing varying interests in the unit. Dr. Adegoke, an MD from Nigeria, also has a PhD in Epidemiology and is current the coordinator of our diabetes study in West Africa.  Dr. Ellison, with a PhD in Epidemiology, is coordinating our obesity grant and actively involved in the training of field staff for the Jackson Heart Study, Jackson, MS. He recently demonstrated a growing independence by developing a research proposal as a supplement to Dr. Rotimi’s R01 grants on the genetic of obesity in blacks. His grant received excellent score and has been funded for fours.  In addition, his work evaluating the association between a quantitative trait locus on chromosome 2 and obesity-related phenotypes was recently accepted for present in the next North America Association for the Study of Obesity later this month in Long Beach, California. We hope to continue to attract young bright minority investigator to continue these efforts. 

5.   Revive summer training programs in epidemiology, biostatistics and research protocol development in West Africa. 

This program was developed by Dr. Rotimi during his tenure at Loyola University in Chicago and was funded for three years by the Loyola, CDC and USAID. The possibility of future funding is being discussed with the Fogarty Institute at NIH. While activity, this program created the only opportunity for many West African physicians and other health care workers to be exposed to course in research protocol development and the use of computer technology in the design and analysis of data.

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CURRENT FUNDED RESEARCH ACTIVITIES 

Genetic epidemiology unit of NHGC currently has NIH funding to study the Genetic and environmental determinants of type 2 diabetes, obesity, hypertension and associated risk factors in populations of the African Diaspora.  Since joining Howard University faculty in July of last year (1999), Dr. Rotimi has received funding for five independent projects including two R01 grants (genetics of obesity - PI; Informed consent and the concept of race – Co-PI). 

A.        Genetics of Obesity 

Obesity and its complications are more common among blacks in the US than whites.  The social and biological determinants of this increased risk are poorly understood. Since the prevalence of obesity remains low in West Africa, a founder population for US blacks, contrasts between these populations allow one to test whether the high rate of obesity among African Americans is a result of exposure to higher levels of environmental risk factors, an increased genetic susceptibility, or an interaction between adverse environments and deleterious genes. 

Heritable factors are thought to contribute 20-40% of obesity risk, although to date no large scale studies have examined the molecular basis for this phenomenon among populations of African descent.  Association and linkage analysis now provide powerful tools for defining genetic risk factors and substantial progress is being made in the genetics of obesity.  Large-scale family studies thus become an important priority in the effort to identify the determinants of obesity.

This study builds on an on-going family study in the US and West Africa, we propose to examine the genetics of obesity in blacks.  Familial aggregation and patterns of inheritance will provide indirect evidence on the role of inheritance.  The molecular basis for susceptibility will be examined with association and linkage analysis using reported candidate loci/regions.  Finally, by examining the impact of variant alleles of these candidate genes among genetically related populations in contrasting environments, evidence of potential gene-environment interactions will be sought.   

Specific Aims: 

1. Determine whether the familial aggregation of obesity is influenced by environmental factors by contrasting the distribution of familial correlations of obesity in Maywood, IL, and Idere, Nigeria. 

2. Use segregation analysis to determine the mode of inheritance of the obesity traits in African Americans and Nigerians. 

3. Use association and linkage analyses to study the molecular basis of obesity in these populations with the candidate gene approach.

To accomplish these aims we will: 

1. Use an established collaboration to identify a sample of 400 nuclear families with 4 or more members from Maywood, IL, and 400 families with 4 or more members from Idere, Nigeria, for a total of 800 families and 3,200 individuals.

2. Measure fat mass (FM), fat-free mass (FFM), percent body fat (PBF), weight, height, body mass index (BMI), waist and hip circumferences, resting metabolic rate (RMR), leptin, insulin and glucose in all participants from Maywood and Nigeria.

3. Model the pattern of inheritance of obesity traits in Maywood and Nigeria and assess potential differences observed in these widely contrasting environments.

4. Genotype the following candidate loci for the African-American and Nigerian families: A quantitative trait locus (QTL) on chromosome 7 (ob gene locus), QTL on chromosome 2; pro-opiomelanocortin (POMC); -3-adrenergic receptor (β3-AR); Thyroid hormone receptor genes (TRα and TRβ); Uncoupling protein-2 and -3 (UCP2, UCP3 locus); melanocortin-4 receptor (MC4R locus).

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B. Polymorphisms in the TNF-" and the TNF Receptor Genes in West African (Obese and Nonobese) and African Americans with Non-Insulin Dependent Diabetic Mellitus (TYPE 2 DIABETES)

Leading Investigators:  

Paulette Furbert-Harris, Ph.D.
Gary Ellison, Ph.D.
Charles Rotimi, Ph.D.

Obesity is one of the major risk factors for type 2 diabetes and both diabetes and obesity are risk factors for cardiovascular disease.  Obesity and type 2 diabetes are both global health problems with high prevalence rates in both developed and in developing countries.  The cytokine tumor necrosis factor-alpha (TNF") is overexpressed in obesity and is a candidate for mediating obesity-induced insulin resistance.  Targeted mutations in both the TNF" gene and its receptors resulted in increased insulin sensitivity .  Polymorphisms (particularly the -307 G/A mutation in the TNF" promoter; and the A allele of the TNF receptor 2) in these genes are associated with obesity and insulin resistance.  In this study we will examine these and other polymorphisms in West African (WA) and African American (AA) cohorts with type 2 diabetes, using the PCR-SSCP method.  The polymorphisms detected will be analyzed and sequenced.  A caucasian type 2 diabetes subset will also be analyzed and an immunologically overactive allergic group with high levels of plasma TNF".  Moreover, we will measure the levels of TNF" and soluble TNF receptors 1 and 2 in the WA control and type 2 diabetes group by ELISA analysis.  Eighty three percent of the WA population are non obese. This study group provides an excellent tool with which to analyze the role of TNF" and/or its receptors in relation to insulin resistance and will better define the potential for these genes as candidates mediating the link between obesity and insulin resistance in type 2 diabetes.  Moreover this study offers the opportunity for development of potential therapeutic strategies (both genetic and nongenetic) for type 2 diabetes and obesity.  

C. Africa America Diabetes Mellitus (AADM) Study 

1.To identify and sample 400 sibling pairs diagnosed with type 2 diabetes above the age of 25 years from the African American ancestral populations of Nigeria and Ghana.

2. To identify and sample 200 spouse normoglycemic controls of either affected sibling pair.

3. To determine diabetes disease status on all participants.

4. To obtain detailed demographic, epidemiologic and clinical information on all     enrolled participants using standardized questionnaires and measurement instruments including electronic blood pressure monitor and Bioelectric Impedance Analyzer (BIA) for estimating body composition.

5. To measure related quantitative variables of all enrolled participants using a national reference laboratory.   

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D. In Search Of Susceptibility Genes For Type 2 Diabetes In West Africa (Genome Wide Scan - CIDR) 

1. To conduct a genome scan on all enrolled participants using a 10 cM map of genetic markers. 

2. To conduct statistical analysis on the resulting data from the genome scan including linkage analysis of the ASP based on the probability that siblings share zero, one and two genes IBD at the putative disease locus. In addition, linkage analysis of diabetes-related quantitative traits will be conducted.

3. To type additional markers and conduct further statistical analysis on informative regions from the genome scan data to rule “in” - likely true positive or rule “out” likely true negative results.

4. To fine map informative regions and use all available genome map and sequence data to identify relevant diabetes susceptibility genes.

This CIDR application requesting a 10 cM genome wide scan data on 1045  samples is an essential first step in identification and cloning of relevant African diabetes genes. Through this partnership, the more limited genotyping resources at Howard University can be focused on subsequent fine mapping of putative linkages.

E. Hypertension in Families of African Origin

It is well established that persons of African decent living in the US experience hypertension rates that are double those experienced by US whites.  However, the biological mechanisms underlying this phenomenon are still not understood. In the broadest terms, the increased risk of hypertension among African Americans (AA) could be due to: 1) the result of exposure to higher levels of environmental risk factors; 2) an increased genetic susceptibility or, 3) an interaction between adverse environments and deleterious genes.  This study will attempt to discriminate between these different hypotheses by contrasting the degree of familial aggregation of blood pressure (BP) among individuals of African ancestry living in two distinct environments: West Africa and the US.

1. Determine whether the familial aggregation of BP in black populations is influenced by the overall distribution of environmental factors at the population level by contrasting the distribution of familial correlations of BP, and the familial aggregation of hypertension, in Ibadan and Chicago.

2. Determine the significance of measured environmental correlates of BP in each environment by comparing the relative magnitude of variance components and regression coefficients for probands and their relatives in each population.

3. Use path analysis to obtain estimates of the genetic and cultural heritability of BP within each population, controlling for the clustering of environmental factors at the household level.

These aims will be accomplished by carrying out the following tasks:

1. Within each population, ascertain 120 probands from an established community survey and, using a fixed cluster approach, recruit a minimum of five family members for each proband.

2. For all members of each of the 240 families measure BP and relevant correlates, including obesity, physical activity, urinary sodium (Na)/potassium (K), and social status. 

3. Collect and store plasma and DNA from all subjects in order to facilitate future molecular studies, aimed at evaluating the distribution and consequences of candidate genes for hypertension in the two contrasting populations.

F. Informed Consent and Concepts of Race in Genetic Research

Knowledge of the genetic code and the capacity for large-scale genotyping has fundamentally altered the character of biomedical research.  To advance our understanding of the ethical dimensions of genetic research for diverse populations we will address questions that take into account concerns of the individual, scientific institutions, and the broader community.  Informed consent provides the focus of the ethical exchange between investigators and study participants.  We will use this social interaction as the context for exploring ethical issues associated with the implementation of collaborative international genetic research.  Broader concerns of society will be addressed by examining how genetic identity and race are conceptualized in both the lay and professional communities.

The proposed research builds on an extensive infrastructure of genetic epidemiological field studies being carried out in metropolitan Chicago and Nigeria.  These studies are part of the NIH-funded Chronic Disease Network (CDN) and include investigations of the genetic and epidemiological determinants of hypertension and breast cancer.  Currently, the process of informed consent to participate in international genetics research is not adequately understood.  Simply transferring standard methods of obtaining consent from industrialized societies to developing countries is wholly inadequate, but no reasonable alternatives have yet been developed.  In addition, the manner in which findings are used, and the representation of communities that are being studied to scientific and lay audiences has received very little attention in biomedical research.  A reformulation of the concept of race to accommodate information on sequence variation is urgently needed. 

Objectives 

1. Define existing processes for obtaining informed consent in genetic research on hypertension and breast cancer currently being conducted in metropolitan Chicago and Nigeria

2. Identify mechanisms to ensure culturally appropriate informed consent that are maximally informative and protective for all research participants

3. Examine the ways in which the cataloguing of new DNA polymorphisms interact with and perpetuate current concepts of race, ethnicity and culture

4. Identify mechanisms for appropriate use of the concepts of race, ethnicity and culture in genetic epidemiological research in order to foster the development of effective clinical intervention and access to health care for all ethnic populations.

G.  Jackson Heart Study/National Human Genome Center at Howard University Collaboration

The proposed partnership between the National Human Genome Center at Howard University (NHGC) and Jackson Heart Study (JHS) will achieve several short and long-term goals. In the immediate, it will contribute to the successful establishment of a large well-characterized population-based cohort of African American pedigrees. This national resource has a great potential to contribute to our understanding of the complex interplay between environmental and genetic factors in the etiology of heart, lung and blood diseases.  

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Short-term goals 

Investigators at the NHGC will provide expertise in the following areas: 

1. Family study design
2. Protocol development
3. Community mobilization and involvement in genome research
4. Ethical issues in biomedical research including the development of a culturally sensitive informed consent document for genetic research. 
5. Data management including database development
6. Data analysis and interpretation
7. Manuscript development
8. Training and education of JHS investigators, field and clinic staff

Long-term goals 

1. NHGC investigators will provide genetic epidemiology training to the JHS investigators. With the ongoing molecular revolution, it is paramount to increase the number of minority investigators with genetic epidemiology skills to ensure adequate representation in genomic research.

2. This collaboration between Historically Black Colleges and Universities will facilitate bridge building in several areas including student exchange programs in epidemiology, statistics, genetics, molecular techniques, research designs and ethical issues in biomedical research. Expertise in community mobilization and interpretation of research findings will also be shared.

3.Finally, this historic partnership promises to contribute to attempts at the federal and state levels to increase the number of minority investigators, students and community members participating in biomedical research. In the long run, this goal should help reduce the health disparities that currently exist in ethnic minority groups in this country. 

CONSULTANT

1) Breast cancer genetics in blacks of African descent: A search for high-risk alleles on two continents. PI: Dr. Funmi Olopade; University of Chicago. Co-PI: Clement Adebamowo; University College Hospital, Ibadan, Nigeria   

2) Jackson Heart Study – Genetics of CVD in African American pedigrees. 

3) Morehouse School of Medicine – Cardiovascular Research Unit (Dr. Elizabeth Ofili)

 GRANTS 

 (1)               GENETICS OF OBESITY (R01-NIDDK/NIH – Principal Investigator).                                                            

The goal of this project is to develop a family study of African Americans and Nigerians to identify genetic factors that contribute to risk of obesity in a cross-cultural setting. We will model the pattern of inheritance of obesity in a cross-cultural setting with widely contrasting environments. In addition to newly reported genes, we proposed to evaluate the role of the following candidate genes, a quantitative trait locus (QTL) on chromosome 7 (ob gene locus), QTL on chromosome 2; pro-opiomelanocortin (POMC); beta3-adrenergic receptor (beta3-AR); Thyroid hormone receptor genes (TR-beta and TR-alpha); Uncoupling protein-2 and -3 (UCP2, UCP3 locus); melanocortin-4 receptor (MC4R locus)

(2)               AFRICA AMERICA DIABETES MELLITUS (AADM) STUDY (Principal Investigator)

The purpose of this study is to map type 2 diabetes genes in West African ancestral populations of African-Americans, through an international collaboration between West African and US investigators. This ongoing collaboration has enrolled and examined 400 Affected sib-pairs along with 200 unaffected spouse controls from West Africa, with two sites in Ghana (Accra and Kumasi) and three in Nigeria (Enugu, Ibadan and Lagos). The next phase is to enroll other family members of the affected sibling pairs to develop a series of nuclear and extended pedigrees. Our strategy is to develop a database containing high quality demographic, epidemiologic and pedigree information in conjunction with blood samples collected for biological assessment and isolation of high quality DNA for whole genome scans.  This international collaborative effort brings together the expertise of investigators from multiple disciplines including epidemiology, endocrinology and genetics.   Furthermore, the collaboration presents unique opportunities to scientists in developing countries to actively participate in human genome research and will in the future facilitate research activities directed at understanding the etiology of other common complex diseases.

 (3)               ENGAGING AFRICAN COMMUNITIES FOR THE HAPMAP PROJECT (HapMap Project NHGRI/NIH – Principal Investigator

Developing Haplotype Map of the Human Genome: We proposed to design and implement a culturally appropriate community engagement program that will result in the recruitment of subjects in three sub-Saharan populations (Kenya, Nigeria and South Africa) to donate blood for both the Haplotype Map Project and an ongoing research program at Howard University called “Translational Genomics in the African Diaspora” (TgRIAD).  The community engagement plan will involve ethnographic methodologies such as surveying attitudes, running focus groups, and forming community working groups to help identify the risks and benefits associated with participation in the research, and to assist in the development of the informed consent documents

(4)               INFORMED CONSENT AND CONCEPT OF RACE IN GENETIC RESEARCH (Co-investigator)

The goals of this project are to: 1) define existing processes for obtaining informed consent in genetic research on hypertension and breast cancer currently being conducted in metropolitan Chicago and Nigeria; 2) identifymechanisms to ensure culturally appropriate informed consent that are maximally informative and protective for all research participants; 3) examine the ways in which the cataloguing of new DNA polymorphisms interact with and perpetuate current concepts of race, ethnicity and culture; and 4) identify mechanisms for appropriate use of the concepts of race, ethnicity and culture in genetic epidemiological research in order to foster the development of effective clinical intervention and access to health care for all ethnic populations

(5)               GENETICS OF OBESITY IN POPULATIONS OF THE AFRICAN DIASPORA: IMPLICATIONS FOR INCREASED SUSCEPTIBILITY TO BREAST CANCER (Principal Investigator) 

Genetics of obesity in populations of the African Diaspora: Implications for increased susceptibility to breast Cancer. The goal of this study is to enroll 300 multi-generational families of at least 5 persons per family from the Washington, DC and surrounding Maryland communities to study the molecular basis of obesity and the potential contribution of obesity candidates to breast cancer risk. In addition, this study will evaluate the determinants of participation of African Americans in genetic epidemiology studies.

(6)               JACKSON HEART STUDY/NATIONAL HUMAN GENOME CENTER AT HOWARD UNIVERSITY COLLABORATION (Principal Investigator).

            The goal of this project is to contribute to the successful establishment of a large well-characterized population-based cohort of African American pedigrees to the complex interaction between environmental and genetic factors in the etiology of heart diseases and associated complications.  Howard University is expected to provide genetic epidemiology training to Jackson Heart Study investigators and students and increase community participation in biomedical research with the ultimate goal of reducing health disparity

  (7)      GENETIC EPIDEMIOLOGY OF HYPERTENSION IN AFRICAN AMERICAN FAMILIES (Principal Investigator)

Taking advantage of existing collaboration and resources, we propose to determine the contribution of selected genetic and environmental factors to hypertension and BP distribution in large multigenerational population-based African American families enrolled from the Washington, DC communities. This study will provide support to continue our successful pilot effort to establish a randomly ascertained, well-characterized, population-based cohort of AA families with members from at least two generations (Howard University Family Study – HUFS). We plan to enroll 400 multi-generational families with a minimum of five members per family with detail phenotypic and genetic information (using both candidate gene and genome wide approaches).

FUNDED GRANTS - Completed

(1)        IN SEARCH OF SUSCEPTIBILITY GENES FOR TYPE 2 DIABETES IN WEST AFRICA - Principal Investigator

            To conduct a genome scan on 800 affected sibling pairs with type 2 diabetes and 200 controls using a 10 cM map of genetic markers. To conduct statistical analysis on the resulting data from the genome scan including linkage analysis of the ASP based on the probability that siblings share zero, one and two genes IBD at the putative disease locus. In addition, linkage analysis of diabetes-related quantitative traits will be conducted. To type additional markers and conduct further statistical analysis on informative regions from the genome scan data to rule “in” - likely true positive or rule “out” likely true negative results. To sequence informative regions to identify and then clone relevant diabetes susceptibility genes 

(2)        HYPERTENSION IN FAMILIES OF AFRICAN ORIGIN.  (Principal Investigator).

            Goals are: 1.) Determine whether the familial aggregation of BP in black populations is influenced by the overall distribution of environmental factors at the population level by contrasting the distribution of familial correlations of BP, and the familial aggregation of HTN, in Ibadan and Chicago. 2.) Determine significance of measured environmental correlates of BP in each environment.  3.) Use path analysis to obtain estimates of the genetic and cultural heritability of BP within each population.

(3)        ETHICAL ISSUES IN THE CONDUCT OF GENETIC EPIDEMIOLOGY RESEARCH ON COMPLEX DISEASE: A STUDY OF INFORMED CONSENT PROCEDURES IN URBAN AND RURAL NIGERIA. (NHGRI/NIH – Principal Investigators)

Describe the formal structures in place for ethical review of the genetic epidemiological research protocols in Chicago, Illinois, and in urban (Lagos and Ibadan) and rural (Igbo-Ora) sites in Nigeria. Design, pre-test and implement a survey addressing subjects’ understanding of and response to informed consent for participation in genetic epidemiological research on hypertension, Type-II diabetes, and breast cancer in Chicago, Illinois, and in Lagos, Ibadan and Igbo-Ora, Nigeria.  Drawing on concepts from behavioral decision theory, this survey will examine the influence of a potential subject’s understanding of research goals, perceptions of the risks and benefits of participating in the research, reasons for consent or refusal to participate in the study, and satisfaction with the consent discussion.  The stratified sample of three patient populations allows for an assessment of informed consent for genetic epidemiological research on diseases that differ in terms of the availability of treatments and the degree to which they are perceived to be life threatening.

(4)        HYPERTENSION IN POPULATIONS OF WEST AFRICAN ORIGIN (Co-investigator).

Goals are: 1.) To complete and analyze cross-sectional data on blood pressure and risk factors in 12,000 adults from three populations (West Africa, The Caribbean and The US). 2.) To extend survey to Caribbean migrants in the United Kingdom.  3.) To perform detailed studies on the origin of hypertension in the source population - Africa. 4.) Evaluate trends in BP over a four year period.  5.) Determine prevalence of CV sequelae and conduct a follow-up study of the 12,000 participants enrolled in the previous period. 6.) Recruit/examine families in each population. 7.) Determine the frequency of DNA markers in sub-sample from each site to establish genetic distance. 8.) Study candidate genes for hypertension to assess potential contributed to risk.

(5)        THE GENETICS OF HYPERTENSION IN BLACKS. (Co-investigator)

            Goals are: 1) determine the contribution of genes underlying the renin-angiotensin system in each population and, by contrasting the results between populations, estimate the degree to which genotype-environmental interactions contribute to hypertension among African Americans.  2.) Use family studies to evaluate the extent to which candidate genes for the renin-angiotensin system co-segregate with hypertension, as well as the intermediate phenotypes.

(6)        FIELD CENTER: GENETICS OF HYPERTENSION (CO-INVESTIGATORS).

Goals are: 1.) Conduct training and monitor quality control of the epidemiologic field. 2.) Collect BP related phenotypic data and DNA on 200 African-American sibships. 3.) Make available DNA from 3,500 persons of African descent. 4.) Initiate study of candidate genes involving the renin-angiotensin system and assay circulating hormone levels for the network.  5.) Oversee data management for the two field centers, and participate in the analysis of the epidemiologic data.

(7)         GENETIC DETERMINANT OF HYPERTENSION (ROCHE MOLECULAR SYSTEMS –   Principal Investigators)

The goals of this project are to assist the research community in identifying the most important genetic markers for CVD. Of particular interest are those genes for which phenotypic measurements (e.g., protein levels or activity) are variable for any individual or generally difficult to measure. In addition, this project will develop a clinically informative panel of genetic markers for CVD. This panel will be used in conjunction with current serum cholesterol measurements. For an affected individual, this information may be used to determine most effective treatment. For family members of an affected person, this information could be used to estimate genetic disposition to premature CVD and consequently suggest certain lifestyle precautions. 

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