Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic celiac disease is estimated to be 1:7. Some complications of celiac disease include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. The only treatment is a gluten-free diet, so that recurrence of symptoms and complications may occur after minor dietary indiscretions. Identifying the underlying genetic causes of celiac disease may allow us to identify susceptible individuals, as well as advance new ways to prevent the disease and to treat it once it occurs. Several genome-wide linkage studies and one genome-wide association study of celiac disease have been conducted. Other than the common locus at HLA, few putative celiac disease loci have been replicated between studies, suggesting that the disease is heterogeneous and complex. A portion of the genetic predisposition can be attributed to HLA, but the etiology is likely due to a number of rare, high penetrant genes (as would be identified in linkage analysis) and to more common, low penetrant genes (as would be identified in association studies). The objective of this study is to identify new loci that increase risk to develop celiac disease. We will capitalize on existing North American resources, including two large collections of celiac cases and controls (Aim 1) and an independent set of celiac cases and their families (Aim 3). We propose a comprehensive multi- stage approach, with the following specific aims.
In Aim 1, we will conduct a genome-wide association (GWA) study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). The GWA will include1900 disease cases and 3400 matched controls, genotyped using the Illumina Human 610-quad chip. Statistical analyses will be performed to test for associations with celiac disease.
In Aim 2, we will conduct a combined analysis of our GWA dataset from Aim 1 and a previous GWA dataset to identify additional low- penetrance loci.
In Aim 3, we will attempt to replicate significant findings from the GWA study in two independent sample sets. At the conclusion of this study, we expect to have validated a number of SNPs and CNPs from regions in the genome that alter the risk of developing celiac disease. These SNPs may prove useful at both the clinical and research level. The data from the study will be shared with the scientific community.

Public Health Relevance

This proposal is focused on identifying genes that increase risk to develop celiac disease, a common disease with a population prevalence of almost 1% (1:133) in the United States. Celiac disease is associated with significant morbidity and mortality, and the only therapy is a gluten-free diet, which places a significant dietary burden on the affected individual. The identification of underlying genetic causes for the disease will allow us to identify susceptible individuals, as well as possibly identify better ways to prevent the disease from occurring and to treat it once it occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK081645-02S1
Application #
8105657
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Karp, Robert W
Project Start
2010-08-01
Project End
2011-01-31
Budget Start
2010-08-01
Budget End
2011-01-31
Support Year
2
Fiscal Year
2010
Total Cost
$753,221
Indirect Cost
Name
University of California Irvine
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ahn, Richard S; Garner, Chad (2015) A Case Study of Fixed-Effects and Random-Effects Meta-Analysis Models for Genome-Wide Association Studies in Celiac Disease. Hum Hered 80:51-61
Mistry, Vanisha; Bockett, Nicholas A; Levine, Adam P et al. (2015) Exome sequencing of 75 individuals from multiply affected coeliac families and large scale resequencing follow up. PLoS One 10:e0116845
Garner, Chad; Ahn, Richard; Ding, Yuan Chun et al. (2014) Genome-wide association study of celiac disease in North America confirms FRMD4B as new celiac locus. PLoS One 9:e101428
Ahn, Richard; Ding, Yuan Chun; Murray, Joseph et al. (2012) Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci. PLoS One 7:e36926
Garner, Chad (2011) Confounded by sequencing depth in association studies of rare alleles. Genet Epidemiol 35:261-8
Dubois, Patrick C A; Trynka, Gosia; Franke, Lude et al. (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295-302