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Published at www.nejm.org December 10, 2008 (10.1056/NEJMoa0807917)

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ABSTRACT

Background Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared.

Methods We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent–child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects.

Results Three celiac disease loci — RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25 — were associated with type 1 diabetes (P<1.00x10^–4). The 32-bp insertion–deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10^–8) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease.

Conclusions A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases.

Source Information

From the Juvenile Diabetes Research Foundation–Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (D.J.S., V.P., N.M.W., J.D.C., K.D., J.H.M.Y., J.M.M.H., H.S., D.G.C., J.A.T.); the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin (R.M.); the Genetics Department, University Medical Center and Groningen University, Groningen, the Netherlands (C.W.); and the Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London (G.A.H., P.C.D., K.A.H., D.A.H.).

This article (10.1056/NEJMoa0807917) was published at www.nejm.org on December 10, 2008. It will appear in the December 25 issue of the Journal.

Address reprint requests to Dr. Todd at the Juvenile Diabetes Research Foundation–Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom, or at john.todd{at}cimr.cam.ac.uk.

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