Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. - PubMed - NCBI
J Autoimmun. 2015 Apr 27. pii: S0896-8411(15)00044-X. doi: 10.1016/j.jaut.2015.03.006. [Epub ahead of print]
Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.
Tomer Y1,
Dolan LM2,
Kahaly G3,
Divers J4,
D'Agostino RB Jr4,
Imperatore G5,
Dabelea D6,
Marcovina S7,
Black MH8,
Pihoker C9,
Hasham A10,
Hammerstad SS10,
Greenberg DA11,
Lotay V12,
Zhang W12,
Monti MC13,
Matheis N3;
SEARCH for Diabetes in Youth Study.
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. Published by Elsevier Ltd.
KEYWORDS:
Gene; Graves' disease; HLA; Hashimoto's thyroiditis; Type 1 diabetes
- PMID:
- 25936594
- [PubMed - as supplied by publisher]
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