The training goal for this ambitious proposal is to provide the fellow, in a stepwise fashion, with increasing levels of independence and responsibility in an interdisciplinary study of complex disease. The research goal of this proposal is to identify the genetic variants which confer susceptibility to type 2 diabetes mellitus (T2DM) in African Americans and gain insight into their mechanism of action. This goal will be attained through 1) Replication of significant findings identified from the genome wide association (GWA) analysis of >650,000 SNPs for association with T2DM, 2) Validation of T2DM associations and exploration of the physiological mechanism through which these variants modulate T2DM susceptibility in additional populations, 3) Fine mapping of the genomic regions consistently showing association with T2DM and identifying trait predisposing variants and ultimately 4) Utilize molecular biology techniques to determine the biological mechanism through which identified T2DM-susceptibility variants exert their effects in vivo. These experiments will provide confirmation of involvement in disease progression and determine the role of these loci in vivo. Taken together, this proposal integrates modern genomic approaches, clinical methodologies and biochemical assays to increase the likelihood of identifying genes which contribute to T2DM susceptibilty. With this approach, the fellow will be supported to develop independence through a comprehensive network of interactive researchers in the fields of epidemiology, statistics, biochemistry, physiology. This will provide the skills and experience to independently direct an interdisciplinary study of the genetics of common disease.

Public Health Relevance

The goal of this project is to identify genes involved in the development of T2D in African Americans. This knowledge wil potentially identify undiscovered disease mechanisms, allow early detection and intervention for individuals at increased risk of developing T2D and aid in the development of novel therapeutics for prevention and treatment of this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Mckeon, Catherine T
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa et al. (2016) Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. Am J Hum Genet 99:56-75
Palmer, Nicholette D; Ng, Maggie C Y; Langefeld, Carl D et al. (2015) Lack of Association of the APOL1 G3 Haplotype in African Americans with ESRD. J Am Soc Nephrol 26:1021-5
Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897
Cooke Bailey, Jessica N; Palmer, Nicholette D; Ng, Maggie C Y et al. (2014) Analysis of coding variants identified from exome sequencing resources for association with diabetic and non-diabetic nephropathy in African Americans. Hum Genet 133:769-79
Bailey, Jessica N Cooke; Lu, Lingyi; Chou, Jeff W et al. (2013) The Role of Copy Number Variation in African Americans with Type 2 Diabetes-Associated End Stage Renal Disease. J Mol Genet Med 7:61
Palmer, Nicholette D; Musani, Solomon K; Yerges-Armstrong, Laura M et al. (2013) Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 58:966-75
Palmer, Nicholette D (author list too long to display - see original citation for additional authors) (2012) A genome-wide association search for type 2 diabetes genes in African Americans. PLoS One 7:e29202
Cooke, Jessica N; Ng, Maggie C Y; Palmer, Nicholette D et al. (2012) Genetic risk assessment of type 2 diabetes-associated polymorphisms in African Americans. Diabetes Care 35:287-92
Palmer, Nicholette D; Hester, Jessica M; An, S Sandy et al. (2011) Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant. Diabetes 60:662-8
Wagenknecht, Lynne E; Palmer, Nicholette D; Bowden, Donald W et al. (2011) Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study. Liver Int 31:412-6

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