Celiac.com 12/12/2008 - For some time now scientists have been working to better understand the connection between celiac disease and diabetes.
About 10% of children and 2% of adults with Type 1 diabetes also have celiac disease, as compared to just 1% of the general population. Moreover, celiac disease and diabetes are known to have a common genetic susceptibility locus in the HLA system, specifically, HLA class II alleles on chromosome six.
The primary susceptibility genes for type-1 diabetes are HLA-DQB1 and HLA-DRB1, but they act in combination with non-immune system genes as well as environmental factors that are still undiscovered. Celiac disease also has a major susceptibility gene in the HLA system — HLA-DQB1 — as well as locations outside the HLA complex.
Recently, a research team led by John Todd, Ph.D., of the University of Cambridge, set out to better understand the connection between the two diseases, and to determine if they shared any non-HLA regions. They discovered another seven regions outside of the HLA system that are tied to both celiac disease and diabetes.
One of those regions is the 32-base pair insertion-deletion variant on chromosome three that leads to a non-functional CCR5 receptor on T cells. People who carry both pairs of these genes enjoy some protection against HIV infection, and its role in both celiac disease and diabetes indicates that lymphocytes are a key factor in both diseases. Carriers of these genes also face a greater risk of developing either celiac disease or diabetes, or both conditions in their lifetimes.
In genome-wide association studies, eight loci outside the HLA system have been associated with celiac disease. Similarly, 15 non-HLA loci have been linked with Type 1 diabetes.
Dr. Todd and colleagues genotyped single nucleotide polymorphisms (SNPs)—single letter variations in the genetic code—in the eight celiac loci and in the 15 diabetes loci.
They then screened DNA samples from 9,339 control subjects, 2,560 subjects with celiac disease, and 8,064 subjects with diabetes. They also tested the diabetic children, along with both biological parents in 2,828 families. The overall statistical significance was P<1.00×10−4.
At the same level of significance, three celiac disease locations—RGS1 on chromosome one, IL18RAP on chromosome two, and TAGAP on chromosome six—were also associated with Type 1 diabetes. The minor alleles of IL18RAP and TAGAP were associated with some protection from in Type 1 diabetes, but were associated with susceptibility in celiac disease.
The CCR5 variant on chromosome three was newly tied to Type 1 diabetes (at P=1.81×10−8) and was also tied with celiac disease, together with PTPN2 on chromosome 18 and CTLA4 on chromosome two. Counting SH2B3 on chromosome 12, which already known to be a shared locus—the number of non-HLA areas strongly tied to both celiac disease and diabetes stands at seven.
Dr. Todd and colleagues said it's possible that a common genetic background with respect to autoimmunity and inflammation—combined with disease-specific variation at HLA and non-HLA genes as well as non-genetic factors -- might lead to different clinical outcomes. It is possible that dietary exposure to gluten in the form of cereal grains might play a role in the pathogenesis of Type 1 diabetes.
These findings offer support a growing scientific view that many common diseases share genetic risk factors, and indicate that celiac and diabetes may in fact have common biological causes, and that the two disorders may be more closely linked than previously understood.
More research is needed to determine which shared risk factors might reveal previously unexpected biologic connections between diseases.
New England Journal of Medicine 2008; 359: 2767-77, 2837-2838