Shared and distinct genetic variants in type 1 diabetes and celiac disease

N Engl J Med. 2008 Dec 25;359(26):2767-77. doi: 10.1056/NEJMoa0807917. Epub 2008 Dec 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antigens, CD
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytoskeletal Proteins
  • IL12A protein, human
  • IL18RAP protein, human
  • IL2RA protein, human
  • Interleukin-12 Subunit p35
  • Interleukin-18 Receptor beta Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • LNK protein, human
  • LPP protein, human
  • Proteins
  • RGS Proteins
  • RGS1 protein, human
  • Receptors, CCR5
  • PTPN2 protein, human
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22