TY - JOUR
T1 - Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes
AU - on behalf of the SEARCH for Diabetes in Youth Study
AU - Tomer, Yaron
AU - Dolan, Lawrence M.
AU - Kahaly, George
AU - Divers, Jasmin
AU - D'Agostino, Ralph B.
AU - Imperatore, Giuseppina
AU - Dabelea, Dana
AU - Marcovina, Santica
AU - Black, Mary Helen
AU - Pihoker, Catherine
AU - Hasham, Alia
AU - Hammerstad, Sara Salehi
AU - Greenberg, David A.
AU - Lotay, Vaneet
AU - Zhang, Weijia
AU - Monti, Maria Cristina
AU - Matheis, Nina
N1 - Publisher Copyright:
© 2015.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Gene
KW - Graves' disease
KW - HLA
KW - Hashimoto's thyroiditis
KW - Type 1 diabetes
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U2 - 10.1016/j.jaut.2015.03.006
DO - 10.1016/j.jaut.2015.03.006
M3 - Article
C2 - 25936594
AN - SCOPUS:84931008634
SN - 0896-8411
VL - 60
SP - 32
EP - 39
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -