Genetics of Type 2 Diabetes in West Africans

Study Overview
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Brief Summary
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Background: Type 2 diabetes (T2D) and associated complications are major contributors to the global disease burden. T2D is already a major health threat in populations in developed countries and is rapidly taking hold in the developing world. It is believed that understanding the complex interplay between genetic and lifestyle characteristics in the etiology of T2D and related complications will lead to the development of better preventive and therapeutic strategies. In Addition, the results of this project will facilitate our understanding of causes of diabetes in African Americans, other US and world populations Objectives: To conduct a genome-wide association study (GWAS) to identify susceptibility genetic variants for diabetes among the Yoruba people in Ibadan, Nigeria. To enroll and examine 300 unrelated cases of T2D and 300 ethnicity-matched Yoruba controls. To conduct resequencing of positional candidate gene/loci to identify likely functional variants in a subset of the cohort. To conduct replication studies of the top-100 scoring variants in three independent African and European ancestry samples. To investigate whether diabetes-associated variants discovered in European populations increase diabetes risk in West Africans. Eligibility: Patients 18 years of age with confirmed T2D who are newly diagnosed or on treatment of Yoruba ethnicity in Ibadan, Nigeria. Control subjects are nondiabetics ethnically matched to patients. Design: The study design for both patients and controls consists of the following steps: Discuss informed consent process and obtain signed informed consent form. Informed consent will be administered by trained clinic staff. Assign study ID (barcode) Administer questionnaires Obtain spot urine sample Measure blood pressure Obtain anthropometric measurements including body composition Perform finger prick for blood glucose level Obtain venous blood samples Perform eye examination On the following day, perform confirmatory blood glucose for the small subset of participants requiring confirmation of previous test result DNA extraction of stored samples will be done at either the National Institutes of Health or the laboratory in Nigeria. GWAS will be conducted using publicly available software packages.

Detailed Description
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This research protocol is designed to study the genetic basis of Type 2 Diabetes (T2D) and related conditions in Africa. This project, the Africa America Diabetes Mellitus (AADM) Study, has been continuously funded for over a decade by multiple institutes at NIH including an R01 grant from the NIDDK to Dr. Rotimi when he was a Professor at Howard University. As a result, the AADM study has a well-established international infrastructure with long-standing collaborators. While previous phases of this study have included related individuals, we are currently only enrolling unrelated T2D cases and controls in order to facilitate genome-wide association studies (GWAS) or similar types of genetic analyses for which unrelated datasets are optimal. In total, we anticipate enrolling 10,000 cases and controls from 5 centers in West Africa (Enugu, Ibadan and Lagos in Nigeria; Accra and Kumasi in Ghana). By sampling from these regions, we will be enrolling individuals representing primarily 4 major ethnic groups (the Yoruba, Ibo, Akan, and Ga), as well as a low number of individuals from a variety of other ethnic groups. To date, we have enrolled 6,486 individuals. These data will be used for a variety of genetic analyses, including association studies based on genome-wide array data, exome chip array and candidate gene/loci datasets, linkage disequilibrium (LD) mapping, and functional studies in different ethnically-defined populations. At each site, efforts will be made to enroll ethnically balanced cases and controls with the goal of facilitating the conduct of GWAS and candidate gene/loci studies in a broad range of populations. To further understand the complex metabolic background of T2D and its consequences, this data will also be explored with respect to a variety of T2D-related traits, including obesity, hypertension, serum lipids, inflammation, nephropathy, and neuropathy. Additionally, these samples will be used to study genetic variation in the context of how participants of different ancestry respond to drugs and other environmental factors and how this variation may have shaped population history. Overall, these studies aim to further our understanding of the genetic basis of T2D in African individuals. Given past activities, it is also anticipated that this resource will form the basis of multiple collaborations between Dr. Rotimi s lab, several NIH intramural researchers and non-NIH scientists. It is hoped that, over time, additional populations from Africa and beyond may be added to this study to expand the focus on individuals from varying ancestral backgrounds; each subsequent population will use the same procedures as in the ongoing work among Africans.

Official Title
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Genetics of Type 2 Diabetes in Diverse Populations

Conditions
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Hypertension, Diabetes

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Cases - Men and women with confirmed type 2 diabetes mellitus that are either on treatment for diabetes or newly diagnosed with blood sugar reading on more than one occasion exceeding or equal to 126 mg/dl. These persons must be above the age of 118 years. In this regard, all newly diagnosed participants will be required to visit the clinic on the following day to perform a fasting blood glucose test to confirm previous results. Controls Men and women with fasting plasma glucose (FPG) less than 100 mg/dl (5.6 mmol/l). Controls must be above age 18 years and should be ethnically matched to the cases. Enrolled cases and controls have to be unrelated. Therefore, only one person may be enrolled from each family unless they are husband and wife. Attempts will be made to enroll an equal number of men and women. To ensure that ethnic distribution is maintained in each study, we are proposing to enroll ethnically-matched participants relevant to each study. EXCLUSION CRITERIA: People who do not meet the above criteria (e.g., younger than 18, without the blood sugar requirements, etc). No more than one non-spouse member of each family. No prisoners, pregnant women or fetuses will be included in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Control<br>Control subjects are nondiabetics ethnically matched to patients | |
| T2D<br>Patients with confirmed T2D who are newly diagnosed or on treatment in Ibadan, Nigeria | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| I | In a subset of participants, to investigate the relationship between diets, gut microbiota, and T2D/related traits. | ongoing | 
| H | To investigate whether hemoglobin A1c (HbA1c) as an indicator of blood glucose control over time is reliable in the presence of the sickle cell trait (HbS), a common hemoglobinopathy in West Africa. The association between HbA1c repeated measures and changes in T2D-related traits over time will be evaluated. We will also evaluate if there is a systematic difference (bias) in the estimation of A1c in carriers of the sickle trait and non-carriers in persons with and without diabetes. | ongoing | 
| G | g- In a subset of participants, to investigate key tissues in the pathophysiology of T2D, we will study differences in the gene expression of skeletal muscle and adipose tissue in lean and obese individuals with and without T2D (n=100, Biopsy Substudy). | ongoing | 
| F | f- To conduct population genetic analyses to describe population history and to develop statistical techniques appropriate for genetic analysis of African ancestry individuals. | ongoing | 
| E | e-To describe these individuals epidemiologically in terms of metabolic traits and the prevalence of relevant conditions, as, for some traits, this may be the first large-scale epidemiological, population-based study of Africans with the appropriate data for such description. | ongoing | 
| D | d- To conduct trans-ethnic fine mapping to determine whether the reduced LD across the genome in African ancestry individuals can refine the region of interest around genetic associations discovered in populations of non-African ancestry. To conduct candidate gene resequencing, Whole Genome Sequencing (WGS), or Whole Exome Sequencing (WES), as funding allows, in participants with metabolic profiles of interest. For instance, individuals will be selected who have extreme values for serum lipids for WES. Variants identified by this resequencing will be genotyped in the larger study population for association analysis. | ongoing | 
| C | c- To develop a large-scale genetic epidemiological resource for the replication of findings in other studies of related traits in African ancestry and non-African ancestry individuals. | ongoing | 
| B | b- To investigate the contribution of gene x environment interactions in T2D risk and in influencing related traits. These investigations may be conducted on either a hypothesis-driven, locus-specific manner or agnostically, i.e. genome-wide. Environmental variants to be considered include lifestyle factors (e.g. diet, measured by food frequency questionnaires (FFQ), socioeconomic measures, and medications taken. | ongoing | 
| A | a- To conduct genetic association studies of T2D and related traits (including blood pressure, serum lipids, blood glucose, adiposity) in West Africans of diverse ethnic groups. Approaches will include genome-wide association studies (including exome chip data) and candidate gene/loci association analyses. | ongoing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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African, Natural History