Autoimmune Thyroiditis and Diabetes: Dissecting the Joint Genetic Susceptibility in a Large Cohort of Multiplex Families

Context: Epidemiological data support a shared genetic susceptibility to autoimmune thyroid disease (AITD) and type 1 diabetes (T1D). Both diseases frequently occur within the same family and in the same individual. Patients developing both T1D and AITD are considered to have an autoimmune polyglandular syndrome type 3 variant (APS3v). Objective: The goals of this study were to identify the joint susceptibility loci/genes for T1D and AITD. Settings: The study was conducted at an academic medical center. Participants and Main Outcome Measures: We used whole genome and candidate gene approaches in a data set of 88 families multiplex for T1D and AITD (448 individuals). Results: We identified three loci, on chromosomes 2p, 6p, and Xp, showing linkage when individuals with either T1D or AITD were classified as affected. The 6p locus contained the human leukocyte antigen class II genes, and the Xp locus contained the FOXP3 gene. Three loci, on 2q, 6p (human leukocyte antigen class II), and Xp, showed evidence for linkage when only APS3v individuals (T1D + AITD) were classified as affected. Analysis of positional candidate genes strongly supported CTLA-4 as the gene on 2q associated with APS3v and FOXP3 as the gene on Xp associated with T1D or AITD and APS3v. In addition, the PTPN22 and insulin variable number tandem repeat genes showed significant associations with T1D or AITD in our families. Conclusions: Our results demonstrate a strong shared genetic susceptibility to T1D and AITD, with most shared genes involved in immune regulation, suggesting that immune dysregulation plays an important role in the joint susceptibility to T1D and AITD. (J Clin Endocrinol Metab 94: 1458-1466, 2009)