HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study

David Hadley, William Hagopian, Edwin Liu, Jin-Xiong She, Olli Simell, Beena Akolkar, Anette G. Ziegler, Marian Rewers, Jeffrey P. Krischer, Wei Min Chen, Suna Onengut-Gumuscu, Teodorica L. Bugawan, Stephen S. Rich, Henry Erlich, Daniel Agardh

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1∗05:01-DQB1∗02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1∗03:01-DQB1∗03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs.METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B,-DRB3,-DRB4,-DPA1, and-DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex.RESULTS:After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1∗04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1∗04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013).CONCLUSIONS:HLA-DPB1∗04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

Original languageEnglish (US)
Pages (from-to)915-920
Number of pages6
JournalAmerican Journal of Gastroenterology
Volume110
Issue number6
DOIs
StatePublished - Jun 10 2015

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Celiac Disease
HLA Antigens
Autoimmunity
Autoantibodies
Gene Frequency
Single Nucleotide Polymorphism
Confidence Intervals
Genetic Heterogeneity
Ambulatory Care
Type 1 Diabetes Mellitus
Logistic Models
Alleles
Odds Ratio
transglutaminase 2

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study. / Hadley, David; Hagopian, William; Liu, Edwin; She, Jin-Xiong; Simell, Olli; Akolkar, Beena; Ziegler, Anette G.; Rewers, Marian; Krischer, Jeffrey P.; Chen, Wei Min; Onengut-Gumuscu, Suna; Bugawan, Teodorica L.; Rich, Stephen S.; Erlich, Henry; Agardh, Daniel.

In: American Journal of Gastroenterology, Vol. 110, No. 6, 10.06.2015, p. 915-920.

Research output: Contribution to journalArticle

Hadley, D, Hagopian, W, Liu, E, She, J-X, Simell, O, Akolkar, B, Ziegler, AG, Rewers, M, Krischer, JP, Chen, WM, Onengut-Gumuscu, S, Bugawan, TL, Rich, SS, Erlich, H & Agardh, D 2015, 'HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study', American Journal of Gastroenterology, vol. 110, no. 6, pp. 915-920. https://doi.org/10.1038/ajg.2015.150
Hadley, David ; Hagopian, William ; Liu, Edwin ; She, Jin-Xiong ; Simell, Olli ; Akolkar, Beena ; Ziegler, Anette G. ; Rewers, Marian ; Krischer, Jeffrey P. ; Chen, Wei Min ; Onengut-Gumuscu, Suna ; Bugawan, Teodorica L. ; Rich, Stephen S. ; Erlich, Henry ; Agardh, Daniel. / HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study. In: American Journal of Gastroenterology. 2015 ; Vol. 110, No. 6. pp. 915-920.
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title = "HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study",
abstract = "Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1∗05:01-DQB1∗02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1∗03:01-DQB1∗03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs.METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21{\%} (n=1,813) carried DR3-DQ2/DR3-DQ2, 39{\%} (n=3,359) carried DR3-DQ2/DR4-DQ8, 20{\%} (n=1701) carried DR4-DQ8/DR4-DQ8, and 17{\%} (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B,-DRB3,-DRB4,-DPA1, and-DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex.RESULTS:After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5{\%}, HLA-DPB1∗04:01 was inversely associated with CDA by conditional logistic regression (AF=44{\%}, odds ratio=0.71, 95{\%} confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1∗04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95{\%} CI=0.73-0.96, P=0.013).CONCLUSIONS:HLA-DPB1∗04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.",
author = "David Hadley and William Hagopian and Edwin Liu and Jin-Xiong She and Olli Simell and Beena Akolkar and Ziegler, {Anette G.} and Marian Rewers and Krischer, {Jeffrey P.} and Chen, {Wei Min} and Suna Onengut-Gumuscu and Bugawan, {Teodorica L.} and Rich, {Stephen S.} and Henry Erlich and Daniel Agardh",
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TY - JOUR

T1 - HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study

AU - Hadley, David

AU - Hagopian, William

AU - Liu, Edwin

AU - She, Jin-Xiong

AU - Simell, Olli

AU - Akolkar, Beena

AU - Ziegler, Anette G.

AU - Rewers, Marian

AU - Krischer, Jeffrey P.

AU - Chen, Wei Min

AU - Onengut-Gumuscu, Suna

AU - Bugawan, Teodorica L.

AU - Rich, Stephen S.

AU - Erlich, Henry

AU - Agardh, Daniel

PY - 2015/6/10

Y1 - 2015/6/10

N2 - Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1∗05:01-DQB1∗02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1∗03:01-DQB1∗03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs.METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B,-DRB3,-DRB4,-DPA1, and-DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex.RESULTS:After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1∗04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1∗04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013).CONCLUSIONS:HLA-DPB1∗04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

AB - Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1∗05:01-DQB1∗02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1∗03:01-DQB1∗03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs.METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B,-DRB3,-DRB4,-DPA1, and-DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex.RESULTS:After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1∗04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1∗04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013).CONCLUSIONS:HLA-DPB1∗04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

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