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 DQA1*03 and by alleles of single nucleotide polymorphisms within the genes DQB1*0302-DQA1*03 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. RESEARCH DESIGN AND 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 TNTF -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.