TY  - JOUR
AB  - OBJECTIVES: The Environmental Determinants of Diabetes in the Young (TEDDY) study follows an HLA-risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in celiac disease autoimmunity (CDA) and CD cumulative incidence for children born between 2004 and 2010. METHODS: Children (n=6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies (tTGA) and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. RESULTS: Individual haplogenotype risks for CDA and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the US, the incidence by age 10 in Colorado was 2.4%. In the HLA, sex, and family history-adjusted model, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared to Finland and Germany, respectively. CONCLUSIONS: There is high regional variability in cumulative incidence of CD which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.
AU  - Stahl, M.*
AU  - Li, Q.*
AU  - Lynch, K.*
AU  - Koletzko, S.*
AU  - Mehta, P.*
AU  - Gragert, L.*
AU  - Norris, J.M.*
AU  - Andrén Aronsson, C.*
AU  - Lindfors, K.*
AU  - Kurppa, K.*
AU  - Ilonen, J*
AU  - Krischer, J.*
AU  - Alkolkar, B.*
AU  - Ziegler, A.-G.
AU  - Toppari, J.*
AU  - Rewers, M.*
AU  - Agardh, D.*
AU  - Hagopian, W.*
AU  - Liu, E.*
C1  - 66325
C2  - 52780
SP  - 539-545
TI  - Incidence of pediatric celiac disease varies by Region: Celiac disease varies by Region.
JO  - Am. J. Gastroenterol.
VL  - 118
IS  - 3
PY  - 2023
SN  - 0002-9270
ER  - 

TY  - JOUR
AB  - OBJECTIVES: 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.
AU  - Hadley, D.*
AU  - Hagopian, W.*
AU  - Liu, E.*
AU  - She, J.X.*
AU  - Simell, O.*
AU  - Akolkar, B.*
AU  - Ziegler, A.-G.
AU  - Rewers, M.*
AU  - Krischer, J.P.*
AU  - Chen, W.M.*
AU  - Onengut-Gumuscu, S.*
AU  - Bugawan, T.L.*
AU  - Rich, S.S.*
AU  - Erlich, H.*
AU  - Agardh, D.*
AU  - TEDDY Study Group (Beyerlein, A.
AU  - Hummel, M.
AU  - Hummel, S.
AU  - Knopff, A.
AU  - Peplow, C.
AU  - Roth, R.
AU  - Stock, J.
AU  - Strauss, E.
AU  - Warncke, K.
AU  - Winkler, C.)
C1  - 44978
C2  - 37133
CY  - New York
SP  - 915-920
TI  - HLA-DPB1*04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study.
JO  - Am. J. Gastroenterol.
VL  - 110
IS  - 6
PB  - Nature Publishing Group
PY  - 2015
SN  - 0002-9270
ER  -