Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 359, Issue 26, Pages 2767-2777Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0807917
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Funding
- Juvenile Diabetes Research Foundation International
- Wellcome Trust
- National Institute for Health Research's Cambridge Biomedical Research Centre
- Celiac UK
- Celiac Disease Consortium
- European Union
- Netherlands Organization for Scientific Research
- Science Foundation Ireland
- Irish Health Research Board
- Hitachi Europe
- NexPep
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [G0000934, G0700545] Funding Source: researchfish
- MRC [G0700545, G0000934] Funding Source: UKRI
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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<1.00 x 10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81 x 10(-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.
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