(From the July 2015 Issue of PediatricsOnline)
Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) — which includes Grave’s disease and Hashimoto’s thyroiditis — are complex, multigenic autoimmune diseases. T1D and AITD are the most common autoimmune disorders, and they share genetic susceptibility, often occurring in the same family or even in the same individual.
The co-occurrence of these diseases in the same patient is classified as a variant of autoimmune polyglandular syndrome type 3 (APS3v). A recent study published in the Journal of Autoimmunity shows that the co-occurrence of AITD and T1D is a unique phenotype with its own genetic susceptibility.
This study is the first genome wide association study (GWAS) performed in patients who developed both T1D and AITD in childhood.
“The identification of the co-occurrence of these diseases as a unique genetic phenotype is a first step in understanding the common genetic forces at work in each of these disease scenarios,” says David Greenberg, PhD, principal investigator in the Battelle Center for Mathematical Medicine in The Research Institute at Nationwide Children’s Hospital and an author on the study. “In order to identify accurately the genetic contributors to a disease or set of diseases, we need to have clearly identified phenotypes to target.”
Investigators identified 21 genes, 16 of which were in the Human Leukocyte Antigen (HLA) region. This result is in line with other studies that have shown that the HLA region is the most important susceptibility locus for both T1D and APS3v.
Several genes specific to the APS3v phenotype were identified, including CTLA-4 and GPR103. The GPR103 gene is of particular interest because it is newly identified as being exclusive to the APS3v phenotype, and its ligand is expressed in thyroid cells. While the GPR103 gene has not previously been associated with autoimmunity, a locus on the same chromosome that is just over 600 Kb downstream was reported to be associated with T1D, rheumatoid arthritis, celiac disease, ulcerative colitis and other autoimmune diseases.
According to the authors, however, it is currently unclear whether this is the same locus as the one associated with APS3v, and further studies are needed to explore this possibility.
Both T1D and AITD are characterized by T-cell infiltration and production of antibodies that attack the target organs. Notably, in this GWAS study, the pathways significantly associated with APS3v include the cell cycle, B-cell development, IL-2 and IL-12 pathways and T-cell function. One non-HLA gene, PTPN22, is known to be a major autoimmunity gene.
“Identifying pathways associated with the disease processes enables the identification of the mechanisms by which these genes predispose to disease, which will hopefully facilitate the development of novel mechanism-based therapeutic strategies,” Dr. Greenberg says.
Tomer Y, Dolan LM, Kahaly G, Divers J, D’Agostino RB Jr, Imperatore G, Dabelea D, Marcovina S, Black MH, Pihoker C, Hasham A, Hammerstad SS, Greenberg DA, Lotay V, Zhang W, Monti MC, Matheis N, on behalf of the SEARCH for Diabetes in Youth Study. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. Journal of Autoimmunity. 2015 Jun;60:32-39.