Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. (June 2015)

• Record Type: Journal Article
• Authors: Tomer, Yaron; Dolan, Lawrence M.; Kahaly, George; Divers, Jasmin; D'Agostino, Ralph B.; Imperatore, Giuseppina; Dabelea, Dana; Marcovina, Santica; Black, Mary Helen; Pihoker, Catherine; Hasham, Alia; Hammerstad, Sara Salehi; Greenberg, David A.; Lotay, Vaneet; Zhang, Weijia; Monti, Maria Cristina; Matheis, Nina
• Is Part Of: Journal of autoimmunity. Volume 60(2015)
• Page Start: 32
• Page End: 39
• Publication Date: 2015-06
• Subjects: Type 1 diabetes -- Graves' disease -- Hashimoto's thyroiditis -- Gene -- HLA; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.03.006
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10 −8 ). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D. Highlights: ∙ Autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D) are genetically associated. ∙ We mapped multiple loci predisposing to T1D + AITD using a genome wide approach. ∙ Sixteen genes were non-HLA genes located in the MHC locus. ∙ We identified GPR103 as a novel susceptibility gene for T1D + AITD. ∙ Major pathways predisposing to T1D + AITD included CD40 and CTLA-4 signaling.