The CRGGH lab is using the admixture mapping approach to identify regions of the genome that may harbor hypertension susceptibility genes in African Americans. We have genotyped a panel of over 3,000 ancestry informative markers in a well-characterized cohort of African Americans enrolled from the Washington, D.C. metropolitan area. This data is being analyzed by investigators at the CRGGH lab. Identified susceptibility loci will be subjected to fine mapping using very high density SNP panel selected from the HapMap database. In combination with bioinformatics methods, the CRGGH lab will use the data from the fine-mapping studies to identify genes to be resequenced for mutation detection and replication studies in multiple populations.

The CRGGH lab is collaborating with Boston University to develop a project to conduct a genome-wide association study in 4,000 African American women (2,000 cases of diabetes and 2,000 controls) in the BWHS. The BWHS is a national longitudinal cohort of women assembled in 1995 to study causes of illness in black women. It includes 59,000 women aged 21-69 at baseline. Dr. Rotimi's lab was responsible for receiving, isolating and tracking DNA samples on these women. Over 25,000 DNA samples have been processed to date.

The CRGGH lab is conducting a large-scale candidate genes study for hypertension (HTN) in African Americans and multiple African populations. A total number of 1,598 subjects (comprising 1,002 African Americans and 562 West Africans) are being genotyped using Illumina's custom SNP GoldenGate genotyping platform. Given the poor consistency of candidate gene studies for HTN, we have given careful thought to the selection of genetic variants represented in the final custom panel of 768 SNPs being genotyped in our sample. The criteria used to select the genes include: (a) Novel genes that have been associated with HTN using admixture mapping (e.g. VNN1), (b) Genes with variants associated with sodium-sensitive HTN and/or show latitudinal cline (e.g. AGT, GNB3, B2AR, GRK4 and the ADDUCIN genes), (c) Genes or variants from high powered genome wide association studies of HTN, including that of the Wellcome Trust Case Control Consortium (WTCCC) (d) Genes from recent fine-mapping studies for HTN (e.g. ATP1B1, RGS5, SELE). Variants selected were tag SNPs that capture the LD structure of each gene, supplemented with non-synonymous coding variants. The resulting data will be used to examine case-control associations for HTN under various genetic models.

As much of the research activities in the CRGGH lab are conducted in vulnerable populations, we are collaborating with investigators at Case Western Reserve University, Howard University and the University of Ibadan in Nigeria, to study issues surrounding informed consent in genetics studies, including voluntary participation and participant comprehension of genetic study purposes. An ongoing international trial project, funded as an R01 grant, is designed to test, and implement a videotaped educational intervention to improve informed consent for genetic epidemiological research on hypertension, breast and colon cancer among African Americans in Washington, D.C., Cleveland, Ohio and Ibadan, Nigeria.

The CRGGH lab is conducting fine mapping of our linkage region on chromosome 5q22-5q31 (109055750 — 128436401 base pairs). Genotyping for this project, funded by NIDDK through an R01 grant mechanism with Dr. Rotimi as the PI before transitioning from Howard University, was conducted by the Center for Inherited Disease Research (CIDR) using the Illumina Custom infinium II BeadChip. A total of 1,536 SNPs were attempted and 1,496 SNPs were released. In addition, we used the Imputation procedure to imputed genotypes using the HapMap release #22 in 60 YRI (Yoruba) founder. This procedure increased the number of SNPs from 1,496 to over 22,000 resulting in much denser genetic map (~ 1kb density from about 11kb). We are currently analyzing this data and initial results are extremely exciting and promise to provide compelling evidences for the identification of novel mechanisms for the development of obesity in recent African and other human populations.

In collaboration with scientists from Ethiopia, the UK and the US, the CRGGH is involved in a Welcome Trust funded project to understand the genetic basis of podoconiosis - a model for gene environment interactions. Podoconiosis (endemic non-filarial elephantiasis) is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. One of the striking features of podoconiosis is that only a small proportion of individuals who are exposed to red clay develop disease.

The CRGGH lab is leading an international team of investigators to understand how inherited factors in combination with lifestyle increase the risk of or resistance to T2D. The name of this novel project is "Africa America Diabetes Mellitus (AADM, pronounced Adam) Study." It is designed to identify diabetes genes in West Africa, the geographical origin of most African Americans. With multiple years of support by NCMHD and other NIH institutes, the AADM project has enrolled more than 4,800 persons with diabetes and control subjects, and it is making significant contributions to the global effort to understand the genetic basis of T2D. In collaboration with colleagues in Iceland (deCODE Genetics), we recently identified three genes that are likely to play a major role in the risk of getting diabetes. The first gene, called TCF7L2, is arguably the most important gene identified for diabetes to date and was identified using the genome-wide association strategy involving thousands of persons with diabetes and control subjects. The second gene, called CDKAL1, influences insulin response. Persons who have two copies of this gene have a blunted insulin response compared with those who carry only one copy or noncarriers. The third gene, TCF2 (HNF1α), associated with increased prostate cancer risk, may confer protection against T2D—an important finding that may help us understand the inverse relationship previously observed between the risk of diabetes and prostate cancer and that may have prevention and treatment implications. Field work is ongoing in five West Africa centers to increase the number of unrelated cases and controls to over 4,000 persons. In addition to the significant contribution that this project is making to understanding the risk factors underlying susceptibility to diabetes, the huge research resources available through the AADM project have facilitated multiple international collaborations, including: 1) an ongoing project in Joan Marini's lab at NICHD on the genetic basis of osteogenesis imperfecta caused by mutation in the LEPRE1 gene; 2) a genome-wide association study of hypertension in African populations in Richard Cooper's lab at Loyola University in Chicago; 3) a study of the genetics of Bardet-Biedl syndrome in African patients—the role of novel mutations in the BBS5 gene; and 4) the population genetics of the hypervariable region of the mtDNA.

In collaboration with investigators at the Coriell Institute for Biomedical Research, the CRGGH lab is using the Affymetrix Genome-Wide Human SNP Array 6.0 with 1.8 million genetic markers (~ equal number of SNPs and CNVs) to perform the first genome-wide association scan of an African-American cohort to search for genes associated with obesity, hypertension, diabetes and the metabolic syndrome. The more than 2,000 persons from multigenerational African-American families included in this project were enrolled and examined by investigators at the CRGGH. The management and analysis of this huge dataset is currently under way at the CRGGH. The investigating team is excited about the anticipated contribution that this large-scale research effort will make to the intense international effort directed at understanding the genetic basis of obesity, hypertension, diabetes and their complications.

The CRGGH lab is working on understanding the role of inflammation in obesity, insulin resistance (IR) and Type 2 diabetes (T2D) in populations of African descent, focusing initially on West Africans and African Americans. Preliminary data based on 315 African Americans and 247 West Africans has shown significant differences between African Americans and West Africans in the association between inflammatory markers and adipokines on one hand with obesity and insulin resistance on the other. We are excited to confirm and expand these preliminary findings in this project by studying larger samples from the study populations, comprising 1,025 African Americans and 1,200 West Africans. Six phenotypic markers of inflammation were selected for study based on their putative roles in the pathophysiology of obesity related co-morbidities as shown in other populations. Our main objectives in this study are: a) to access the relationships between obesity-inflammation -IR, T2D, and other obesity-related traits at phenotypic and genotypic levels, b) to compare the above relationships in the populations of African descent, c) to understand genotype-phenotype variations in obesity-related complications with focus on inflammation.

The CRGGH lab believes that scientific activities operate within the larger context of societies and as a result the junction of society and science has to be constantly managed in order not to trample on the independence required for good scholarly investigation and, maybe more importantly, not to alienate members of our communities from the scientific process. In this regard, the CRGGH lab is interested in how scientists document and describe the non-random pattern of human genetic variation (HGV) and its link to disease risks in different populations. For example, how does HGV inform our understanding of self and group identity? Our lab is directly involved in these debates and will continue to inform the interpretation of HGV within the context of health disparities and group identity.

1. We have been approved and are currently in the field collecting muscle biopsy samples on 30 diabetics and 30 controls to conduct global gene expression profiling to identify susceptibility genes to diabetes and related complications;

2. We are in the process of establishing substantial collaborations that will leverage existing and new biological resources for the conduct of multiple pharmacogenomics projects in U.S. minority populations and African populations.