Type 1 diabetes (T1D) is the second most common chronic disease in children after asthma. T1D is most prevalent in Caucasian populations but also found in other groups, including African Americans. T1D is an autoimmune disease with a strong genetic component, with the largest portion, estimated at approximately 50%, of the genetic susceptibility found in the HLA region of chromosome 6. The association of genes in the HLA region with T1D was noted more than 30 years ago, and much progress has been made in identifying T1D risk factors for Caucasians. However, very little is known about the genetic susceptibility to T1D in African Americans. Our work from the funding period 2003-2008 has positioned our research team to address this important question. The combination of resources generated from our studies with resources generated by the Type 1 Diabetes Genetics Consortium (T1DGC) has allowed preliminary statistical analyses to be performed on African American T1D patients vs. African American controls. These results confirm that the HLA alleles, haplotypes, and genotypes affecting T1D susceptibility in African Americans can be markedly different than those in Caucasians. Our proposed research for this renewal will confirm and augment these results and is structured with four Specific Aims.
Aim 1 is designed to test specific hypotheses, generated by our previous work, for HLA-associated T1D risk of African HLA-DR-DQ haplotypes. We will use both our resources and T1DGC resources and apply both existing and new technologies to address these hypotheses.
Aim 2 is the most exploratory of the 4 Specific Aims and is designed to test the hypothesis that African American T1D patients have a different proportion of Caucasian ancestry than does the general African American population. Ancestry Informative Markers (AIMs) have been used successfully by our colleagues to discover ethnic-specific genomic regions harboring disease susceptibility loci. We will apply this technology to T1D, with assistance from a strong team of collaborators, and expect to identify such regions in T1D for further studies.
Aim 3 is straightforward and is designed to complete the 8-locus, high-resolution genotyping in our population-based sample of samples from 1000 African Americans. This will provide a valuable resource both for our studies and for those of other investigators.
Aim 4 is also a continuation and is designed to continue and accelerate our collection of T1D patients from the ethnically diverse pediatric diabetes patient population in Oakland. These samples will be utilized for Aims 1 and 2 of this proposed research and will provide a foundation for future studies in multiple ethnic groups. Taken together, the research proposed in these 4 aims will help us unravel the complex genetic factors that underlie T1D susceptibility and have not yet been discovered in the underserved and understudied African American population.
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