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.
Deborah J Smyth  1 ,  Vincent Plagnol ,  Neil M Walker ,  Jason D Cooper ,  Kate Downes ,  Jennie H M Yang ,  Joanna M M Howson ,  Helen Stevens ,  Ross McManus ,  Cisca Wijmenga ,  Graham A Heap ,  Patrick C Dubois ,  David G Clayton ,  Karen A Hunt ,  David A van Heel ,  John A Todd
Affiliations
  • 1. 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.
PMID: 19073967 DOI: 10.1056/NEJMoa0807917
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.