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
N1 - Publisher Copyright:
© 2015 by the American College of Gastroenterology.
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.
UR - http://www.scopus.com/inward/record.url?scp=84930757675&partnerID=8YFLogxK
U2 - 10.1038/ajg.2015.150
DO - 10.1038/ajg.2015.150
M3 - Article
C2 - 26010309
AN - SCOPUS:84930757675
SN - 0002-9270
VL - 110
SP - 915
EP - 920
JO - American Journal of Gastroenterology
JF - American Journal of Gastroenterology
IS - 6
ER -
