Risk of celiac disease in children with type 1 diabetes is modified by positivity for HLA-DQB1*02-DQA1*05 and TNF -308A.
OBJECTIVE
The overlap between genetic susceptibility to celiac disease (CD) and to type 1 diabetes is incomplete; therefore, some genetic polymorphisms may significantly modify the risk of CD in subjects with type 1 diabetes. This study aimed to investigate whether the susceptibility to CD in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03 and by alleles of single nucleotide polymorphisms within the genes encoding CTLA4, transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1, IL-2, IL-6, and IL-10.


METHODS
Genotypic data were compared between 130 case subjects (children with type 1 diabetes and CD diagnosed using endomysium antibodies) and 245 control subjects (children with type 1 diabetes only, optimally two per case, matched for center, age at type 1 diabetes onset, and type 1 diabetes duration). The subjects were recruited from 10 major European pediatric diabetes centers performing regular screening for CD. The polymorphisms were determined using PCR with sequence-specific primers, and the risk was assessed by building a step-up conditional logistic regression model using variables that were significantly associated with CD in the univariate analysis.


RESULTS
The best-fitted model showed that risk of CD is increased by presence of HLA-DQB1*02-DQA1*05 (odds ratio 4.5 [95% CI 1.8-11], for homozygosity, and 2.0 [1.1-3.7], for a single dose) and also independently by TNF -308A (1.9 [1.1-3.2], for phenotypic positivity), whereas IL1-alpha -889T showed a weak negative association (0.6 [0.4-0.9]).


CONCLUSIONS
The results indicate that the risk of CD in children with type 1 diabetes is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, the TNF -308A.
Motol University Hospital, Charles University Prague, V Uvalu 84, CZ-150 06, Prague, The Czech Republic.
Zdenek
Z
Sumnik
Ondrej
O
Cinek
Nina
N
Bratanic
Olga
O
Kordonouri
Michal
M
Kulich
Barnabas
B
Roszai
Andras
A
Arato
Jan
J
Lebl
Gyula
G
Soltesz
Thomas
T
Danne
Tadej
T
Battelino
Edit
E
Schober
D000293:Adolescent; D016022:Case-Control Studies; D002446:Celiac Disease / Q000150:complications / Q000235:genetics* / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006801:Humans; D008297:Male; D010641:Phenotype; D012044:Regression Analysis; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D014409:Tumor Necrosis Factor-alpha