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.
INTRODUCTION: Type 1 diabetes is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets.
The disease affects approximately 0.4% of persons of European origin and is strongly clustered in families.
The major susceptibility genes — the HLA class II loci, HLA-DQB1 and HLA-DRB1 on chromosome 6p21 — act in combination with many other non-HLA loci across the genome,1,2 with unknown environmental factors playing a major role.3,4,5,6
Celiac disease, which results from an immune, inflammatory reaction in the small intestine to proteins in ingested barley, wheat, and rye gluten, occurs in approximately 0.1% of persons of northern European origin, an estimate that is based on clinically diagnosed symptoms.
However, within that population, the prevalence of celiac disease may be as high as 1% on the basis of the highly sensitive and specific test for autoantibodies to tissue transglutaminase.7,8 The major susceptibility gene is also HLA-DQB1.9,10
Celiac disease and anti–tissue transglutaminase antibodies occur more frequently in patients with type 1 diabetes than in the general population, depending on the age of the patient; at most, 10% of children and 2% of adults with type 1 diabetes have positive tests for such antibodies.11
An increasing incidence of celiac disease during recent decades has also been reported.8 It has been suggested that gluten consumption, along with gut permeability and inflammation, are factors in the development of type 1 diabetes.6,12 These results suggest that type 1 diabetes and celiac disease may share some causative genetic and environmental factors.
Genomewide association studies have recently identified eight chromosome regions outside the HLA region as being associated with celiac disease (P<5.00x10–7), findings that probably provide a representative view of the major genetic effects in the northern European population for this disorder.10
In patients with type 1 diabetes, 15 non-HLA regions have been established to date,1,13,14,15 and two other loci, IL7R on chromosome 5p13 and CD226 on chromosome 18q22, have been implicated in type 1 diabetes and multiple sclerosis.1,16,17
It has already been reported that the SH2B3 locus on chromosome 12q24 is shared between type 1 diabetes and celiac disease, with indications of such sharing in IL2–IL21 on chromosome 4q27 and CCR3 on chromosome 3p21.9,10
In addition, there is some evidence for association of the established type 1 diabetes loci, CTLA4 on chromosome 2q339,18 and PTPN22 on chromosome 1p13,19 in celiac disease.
In this study, we evaluated the association between all these loci and type 1 diabetes and celiac disease, including the CCR5 32-bp insertion–deletion variant that we report here as a type 1 diabetes locus, in order to assess the genetic similarities and differences between these two inflammatory disorders. (See the Glossary and the
Methods section in the Supplementary Appendix, available with the full text of this article at www.nejm.org.)
Published at www.nejm.org December 10, 2008 (10.1056/NEJMoa0807917)
SEE FULLTEXT
http://content.nejm.org/cgi/content/full/NEJMoa0807917?query=TOC
