Type 1 diabetes, celiac disease share common genetic origin

Autoimmunity-related tissue damage and intolerance to dietary antigens may be etiologic features of these two diseases.

Researchers have identified seven chromosome regions that are shared between type 1 diabetes and celiac disease.

Four type 1 diabetes loci were also associated with celiac disease — PTPN2 on chromosome 18p11, CTLA4 on chromosome 2q33, SH2B3 on chromosome 12q24 and the 32-bp insertion-deletion variant on chromosome 3p21. Three celiac disease loci were also associated with type 1 diabetes — RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12 and TAGAP on chromosome 6q25.

“Our findings and those reported previously provide convincing evidence that 21 non-HLA loci are associated with type 1 diabetes and 11 non-HLA loci are associated with celiac disease,” they wrote in The New England Journal of Medicine.

Further, “the effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease,” they wrote.

In order to assess the genetic similarities and differences between the two inflammatory disorders, the researchers obtained 8,064 samples from people with type 1 diabetes, 2,560 samples from individuals with celiac disease and 9,339 control samples.

“Seven of these chromosome regions are shared between the two diseases, suggesting that for an investigation of shared loci in two diseases that are known to cosegregate, the previous odds of 1000:1 against there being a true association at any tested candidate gene is too conservative,” the researchers wrote.

Underlying mechanisms

“[The researchers] provide an answer to the question of why some families seem to have an undue susceptibility to two autoimmune diseases: type 1 diabetes and celiac disease,” Richard M. Plenge, MD, PhD, a rheumatologist in the division of rheumatology, immunology and allergy at Brigham and Women’s Hospital in Boston, wrote in an accompanying editorial.

These findings suggest that type 1 diabetes and celiac disease may be caused by uncommon underlying mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens. The researchers believe that these regions of the chromosomes regulate the mechanisms that cause the immune system to attack both pancreatic beta cells and the small intestine.

Another hypothesis is that the two autoimmune diseases not only share genetic causes but similar environmental triggers as well.

“Our results support further evaluation of the hypothesis that cereal and gluten consumption might be an environmental factor in type 1 diabetes, leading to alteration of the function of the gut immune system and its relationship with the pancreatic immune system,” they wrote.

“The next step is to understand how these susceptibility genes affect the immune system, and to keep exploring environmental factors that might alter the risk of type 1 diabetes, which results from an incredibly complex interaction between nature and nurture,” John A. Todd, PhD, professor of medical genetics at the University of Cambridge, said in a press release.

“If subsequent studies confirm the highly suggestive associations, then about half the genetic risk alleles that have been identified to date are shared between the two diseases,” Plenge wrote in his editorial. – by Katie Kalvaitis

N Engl J Med. 2008;doi:10.1056/NEJMoa0807917.

This paper is unusual in the large number of families that was used to document cosegregation of celiac disease and type 1 diabetes, and the power provided by these large numbers. As a result the authors document several new genes for which there is cosegregation of the two diseases. Indeed it is remarkable that with these data we now have documentation that eight of the 12 single nucleotide polymorphisms associated with susceptibility to celiac disease also appear to be associated with susceptibility to type 1 diabetes. This would suggest that there may be a lot of previously unrecognized similarity in the initiation and immunopathology of these two diseases. The list of genes provided by this study would provide a great starting point for investigation into specific molecular mechanisms that may be shared between these two diseases.

– Ivan C. Gerling, PhD

Professor of Medicine
University of Tennessee Health Science Center