Celiac disease (CD) is a major public health problem affecting at least 1% of the general population and leading to significant morbidity and mortality. Despite tremendous progress in the past decade, CD is still under-diagnosed due to low awareness and lack of a comprehensive screening program. Applications of highly sensitive and specific serological markers such as autoantibodies to tissue transglutaminase (tTG) suggest that up to 4% of the general population may have CD. The natural history of CD is only partially understood and the boundaries between clinical and subclinical disease remain blurred. While early detection and treatment with gluten-free diet (GFD) seems logical, the evidence is lacking to inform optimal timing, intensity and duration of gluten exclusion. Our unique large prospective study of children at high-risk of CD (R01 DK50979, 9/1995-4/2011, M. Rewers, P.I.) has answered some of the key research priorities identified by expert committees. In this competing renewal application we are proposing to address additional unanswered challenges facing celiac research today:
Specific Aim 1. Determine the cumulative incidence, genetic, and environmental predictors of persistent tTG and CD by age 15 years. We will accomplish this goal through continuing follow-up for development of tTG and CD of already established cohorts: A) General population children with high risk HLA-DQ genotypes (n=1,268;current median age 10.8 yr);B) Non-diabetic first degree relatives of patients with type 1 diabetes (n=1,082;current median age 13.6 yr);C) Children with type 1 diabetes (T1D) (n=4,677); During the proposed 5-year follow-up, 66% of the study participants in cohorts A and B will achieve 15 yrs of age and all will be at least 10. This will allow for a comprehensive assessment of the natural history of CD throughout childhood and adolescence. Our preliminary data suggest that more than 60% childhood CD cases in the U.S. develop after age 5. It is likely that the genetic and environmental causes of CD manifesting in older children differ from those in pre-school children. Future screening programs need to take this into account.
Specific Aim 2. Define predictors of clinically relevant outcomes: growth, micronutrient deficiencies, bone mineralization and quality of life in a large prospective followed cohort of children with screening-identified tTG+ and appropriate controls.
Specific Aim 3. Map out the evolution of humoral response to wheat gliadins and selected glutenins, hordeins and secalins from early childhood to adulthood.

Public Health Relevance

Celiac disease (CD) is a major public health problem affecting at least 1% of the general population and leading to significant morbidity and mortality. Despite tremendous progress in the past decade, CD is still under-diagnosed due to low awareness and lack of a comprehensive screening program. The natural history of CD is only partially understood and the boundaries between clinical and subclinical disease remain blurred. While early detection and treatment with gluten-free diet (GFD) seems logical, the evidence is lacking to inform optimal timing, intensity and duration of gluten exclusion. Our unique large prospective study of children at high-risk of CD has answered some of the key research priorities identified by expert committees. In this competing renewal application we are proposing to: 1) determine the incidence, genetic, and environmental predictors of CD by age 15 years;2) define predictors of clinically relevant outcomes: growth, micronutrient deficiencies, bone mineralization and quality of life of children with screening-identified CD;and 3) map out the evolution of immune response to wheat proteins from early childhood to adulthood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050979-16
Application #
8291233
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Hamilton, Frank A
Project Start
1995-09-30
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
16
Fiscal Year
2012
Total Cost
$327,703
Indirect Cost
$110,203
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Steck, Andrea K; Dong, Fran; Taki, Iman et al. (2014) Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. Diabetes Care 37:2031-3
Steck, Andrea K; Dong, Fran; Wong, Randall et al. (2014) Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers. Pediatr Diabetes 15:355-62
Jin, Yulan; Sharma, Ashok; Bai, Shan et al. (2014) Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function. Diabetes 63:2506-15
Romanos, Jihane; Rosen, Anna; Kumar, Vinod et al. (2014) Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants. Gut 63:415-22
Yu, Liping; Dong, Fran; Miao, Dongmei et al. (2013) Proinsulin/Insulin autoantibodies measured with electrochemiluminescent assay are the earliest indicator of prediabetic islet autoimmunity. Diabetes Care 36:2266-70
Rewers, Marian; Eisenbarth, George S (2012) Autoimmunity: Celiac disease in T1DM-the need to look long term. Nat Rev Endocrinol 8:5-6, 7-8
Stene, L C; Rewers, M (2012) Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies. Clin Exp Immunol 168:12-23
Steck, Andrea K; Wong, Randall; Wagner, Brandie et al. (2012) Effects of non-HLA gene polymorphisms on development of islet autoimmunity and type 1 diabetes in a population with high-risk HLA-DR,DQ genotypes. Diabetes 61:753-8
Simmons, Jill H; Klingensmith, Georgeanna J; McFann, Kim et al. (2011) Celiac autoimmunity in children with type 1 diabetes: a two-year follow-up. J Pediatr 158:276-81.e1
Forlenza, Gregory P; Rewers, Marian (2011) The epidemic of type 1 diabetes: what is it telling us? Curr Opin Endocrinol Diabetes Obes 18:248-51

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