Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort
(2016) In PLoS ONE 11(3). p.0152476-0152476- 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... (More)
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.
(Less)
- author
- Sharma, Ashok
; Liu, Xiang
; Hadley, David
; Hagopian, William
; Liu, Edwin
; Chen, Wei-Min
; Onengut-Gumuscu, Suna
; Simell, Ville
; Rewers, Marian
; Ziegler, Anette-G
; Lernmark, Åke
LU
; Simell, Olli
; Toppari, Jorma
; Krischer, Jeffrey P
; Akolkar, Beena
; Rich, Stephen S
; Agardh, Daniel
LU
and She, Jin-Xiong
(Less) - author collaboration
- organization
- publishing date
- 2016
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 11
- issue
- 3
- pages
- 0152476 - 0152476
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- pmid:27015091
- wos:000372708900069
- scopus:84983038866
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0152476
- language
- English
- LU publication?
- yes
- id
- 490f271a-b548-4dbe-a876-5078c2354c70
- date added to LUP
- 2016-04-18 15:05:14
- date last changed
- 2024-05-18 00:47:24
@article{490f271a-b548-4dbe-a876-5078c2354c70,
abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
author = {{Sharma, Ashok and Liu, Xiang and Hadley, David and Hagopian, William and Liu, Edwin and Chen, Wei-Min and Onengut-Gumuscu, Suna and Simell, Ville and Rewers, Marian and Ziegler, Anette-G and Lernmark, Åke and Simell, Olli and Toppari, Jorma and Krischer, Jeffrey P and Akolkar, Beena and Rich, Stephen S and Agardh, Daniel and She, Jin-Xiong}},
issn = {{1932-6203}},
language = {{eng}},
number = {{3}},
pages = {{0152476--0152476}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort}},
url = {{http://dx.doi.org/10.1371/journal.pone.0152476}},
doi = {{10.1371/journal.pone.0152476}},
volume = {{11}},
year = {{2016}},
}