Type 1 diabetes (T1D), an autoimmune disease with a strong genetic susceptibility component, is the second most common chronic disease in children after asthma, and its incidence is rising. Although T1D is most prevalent in Caucasian populations, it is also found in other groups, including African Americans (AA);however, very few studies on T1D in AA have been reported. Examination of similarities and differences in genetic risk factors for T1D in multiple ethnic groups is critical not only for understanding the pathophysiology of the disease but also for the design of genetic tests with good predictive value specific for the individual being screened. Our work from the funding period 2003-2009 has positioned our research team to address this important question. The combination of data generated from our studies and by the Type 1 Diabetes Genetics Consortium (T1DGC) has allowed preliminary statistical analyses to be performed on AA T1D patients vs. AA controls, producing results that are markedly different than those in Caucasians. Our proposed research for this funding period 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 a combination of our samples, samples from our colleagues at Kaiser and other institutions, and samples from existing collections, and apply both established and new technologies to address these hypotheses.
Aim 2 will test the hypothesis that admixture mapping of our African American cohort will reveal ethnic-specific genetic regions associated with T1D susceptibility. Preliminary data from 106 Ancestry Informative Markers (AIMs) on a small number of patients and controls support this hypothesis and justify more in-depth testing and analysis.
Aim 3 will complete the 8-locus, high- resolution genotyping in our population-based cohort 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 to accelerate our collection of T1D patients from the ethnically diverse pediatric diabetes patient population in Oakland and other centers and to supplement the cohort with African American samples from existing collections, such as the T1DGC, SEARCH, and others. Several new collaborators, including colleagues from Kaiser in Oakland, have agreed to assist with recruitment of this cohort, and we are in the process of obtaining IRB approval from all collaborating sites. The resulting sample set will be the largest known collection of African American T1D samples ever assembled, estimated at >800 patients, and will provide a foundation for future studies in AA and other ethnic groups. Taken together, the research proposed here will help us unravel the complex genetic factors that underlie T1D susceptibility and have not yet been revealed in the underserved and understudied AA population. Our data are expected to lead to the eventual design of genetic screens for T1D appropriate for African Americans.

Public Health Relevance

Type 1 diabetes (T1D), a disease in which insulin-producing cells are destroyed by the body's own immune system, is most prevalent in Caucasians, but it is also found in other ethnic groups. Variation in certain genes is known to make some people more likely to have type 1 diabetes than others. This project will study those genes in African American children, whose genes will have variants not seen in Caucasian children, and compare them to variants already identified, with the aim of refining prediction of disease for both groups and gaining insight into the mechanism of acquiring type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061722-10
Application #
8446995
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Akolkar, Beena
Project Start
2002-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$499,824
Indirect Cost
$168,914
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Valdes, Ana M; Varney, Michael D; Erlich, Henry A et al. (2013) Receiver operating characteristic analysis of HLA, CTLA4, and insulin genotypes for type 1 diabetes. Diabetes Care 36:2504-7
Lipner, E M; Tomer, Y; Noble, J A et al. (2013) HLA class I and II alleles are associated with microvascular complications of type 1 diabetes. Hum Immunol 74:538-44
Noble, Janelle A; Valdes, Ana M (2011) Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep 11:533-42
Noble, J A; Johnson, J; Lane, J A et al. (2011) Race-specific type 1 diabetes risk of HLA-DR7 haplotypes. Tissue Antigens 78:348-51
Andrew, Toby; Calloway, Cassandra D; Stuart, Sarah et al. (2011) A twin study of mitochondrial DNA polymorphisms shows that heteroplasmy at multiple sites is associated with mtDNA variant 16093 but not with zygosity. PLoS One 6:e22332
Noble, Janelle A; Valdes, Ana Maria; Varney, Michael D et al. (2010) HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 59:2972-9
Noble, Janelle A; Martin, Adelle; Valdes, Ana M et al. (2008) Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls. Hum Immunol 69:291-300
Thomson, G; Valdes, A M; Noble, J A et al. (2007) Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 70:110-27
Steenkiste, A; Valdes, A M; Feolo, M et al. (2007) 14th International HLA and Immunogenetics Workshop: report on the HLA component of type 1 diabetes. Tissue Antigens 69 Suppl 1:214-25
Noble, Janelle A; Valdes, Ana M; Lane, Julie A et al. (2006) Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-alpha polymorphisms on type 1 diabetes susceptibility. Hum Immunol 67:999-1004

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