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PLoS One. 2016 Mar 25;11(3):e0152476. doi: 10.1371/journal.pone.0152476. eCollection 2016.

Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort.

Author information

1
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, United States of America.
2
Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, United States of America.
3
Division of Population Health Sciences and Education, St George's University of London, London, United Kingdom.
4
Pacific Northwest Diabetes Research Institute, Seattle, WA, United States of America.
5
Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO, United States of America.
6
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States of America.
7
Department of Pediatrics, University of Turku, Turku, Finland.
8
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States of America.
9
Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany.
10
Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden.
11
National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, United States of America.
12
Diabetes and Celiac Disease Unit, Lund University, Malmo, Sweden.

Abstract

OBJECTIVES:

There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study.

METHODS:

A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses.

RESULTS:

We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10-4>P>5.8x10-6). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10-4). A SNP near PKIA (rs117128341, P = 6.5x10-8, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10-7, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10-6, HR = 0.76 and LPP, P = 2.8x10-5, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10-4); non-HLA genes are therefore involved in development of tTGA.

CONCLUSIONS:

In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.

PMID:
27015091
PMCID:
PMC4807782
DOI:
10.1371/journal.pone.0152476
[Indexed for MEDLINE]
Free PMC Article

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