Risk of Celiac Disease in Children With Type 1 Diabetes Is Modified by Positivity for HLA-DQB1*02-DQA1*05 andTNF −308A
- Zdenek Sumnik, MD, PHD1,
- Ondrej Cinek, MD, PHD1,
- Nina Bratanic, MD2,
- Olga Kordonouri, PHD3,
- Michal Kulich, PHD1,
- Barnabas Roszai, MD4,
- Andras Arato, MD, PHD5,
- Jan Lebl, MD, PHD6,
- Gyula Soltesz, MD, PHD4,
- Thomas Danne, MD7,
- Tadej Battelino, MD, PHD2 and
- Edit Schober, MD8
- 1Motol University Hospital, the Second Medical School, Charles University, Prague, The Czech Republic
- 2University Children’s Hospital, Department of Pediatric and Adolescent Endocrinology, Ljubljana, Slovenia
- 3Clinic of General Pediatrics, Otto-Heubner-Centrum, Charite, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany
- 4Department of Pediatrics, University of Pecs, Pecs, Hungary
- 5First Department of Pediatrics, Semmelweis University, Budapest, Hungary
- 6Department of Pediatrics, The Third Medical School, Charles University, Prague, The Czech Republic
- 7Kinderkrankenhaus auf der Bult, Hannover, Germany
- 8University Children’s Hospital, University of Vienna, Vienna, Austria
- Address correspondence and reprint requests to Ondrej Cinek, MD, PhD, Department of Pediatrics, Motol University Hospital, Charles University Prague, V Uvalu 84, CZ-150 06, Prague, The Czech Republic. E-mail: ondrej.cinek{at}lfmotol.cuni.cz
Abstract
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)-β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, 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 TNF −308A (1.9 [1.1–3.2], for phenotypic positivity), whereas IL1-α −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.
- CD, celiac disease
- IHWC, 13th International Histocompatibility Workshop and Conference
- IL, interleukin
- PCR-SSP, PCR with sequence-specific primers
- SNP, single nucleotide polymorphism
- TNF, tumor necrosis factor
Footnotes
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Z.S. and O.C. contributed equally to this work.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted January 15, 2006.
- Received October 9, 2005.
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