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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<1.00x10(-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.

Original publication

DOI

10.1056/NEJMoa0807917

Type

Journal article

Journal

N Engl J Med

Publication Date

25/12/2008

Volume

359

Pages

2767 - 2777

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD, Autoimmunity, CTLA-4 Antigen, Celiac Disease, Child, Child, Preschool, Cytoskeletal Proteins, Diabetes Mellitus, Type 1, Female, Genetic Linkage, Genetic Predisposition to Disease, Humans, Infant, Interleukin-12 Subunit p35, Interleukin-18 Receptor beta Subunit, Interleukin-2 Receptor alpha Subunit, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Proteins, RGS Proteins, Receptors, CCR5, Young Adult