GENOME WIDE IDENTIFICATION OF NEW GENES AND PATHWAYS IN PATIENTS WITH BOTH AUTOIMMUNE THYROIDITIS AND TYPE 1 DIABETES

Details

• Alternative Title:
  J Autoimmun
• Personal Author:
  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 ; Salehi Hammerstad, Sara ; Greenberg, David A. ; Lotay, Vaneet ; Zhang, Weijia ; Monti, Maria Cristina ; Matheis, Nina
• Description:
  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.
• Subjects:
  Antigens, CD40 Article B-Lymphocytes CTLA-4 Antigen Diabetes Mellitus, Type 1 Gene Genetic Predisposition To Disease Genome-Wide Association Study Graves’ Disease Hashimoto’s Thyroiditis Histocompatibility Antigens Class I Histocompatibility Antigens Class II HLA Humans Linkage Disequilibrium Polyendocrinopathies, Autoimmune Protein Tyrosine Phosphatase, Non-Receptor Type 22 T-Lymphocytes Thyroiditis, Autoimmune Type 1 Diabetes

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• Source:
  J Autoimmun. 2015; 60:32-39.
• Pubmed ID:
  25936594
• Pubmed Central ID:
  PMC4457545
• Document Type:
  Journal Article
• Funding:
  00097/PHS HHS/United States ; 1U18DP002709/DP/NCCDPHP CDC HHS/United States ; 8 UL1 TR000077/TR/NCATS NIH HHS/United States ; DK067555/DK/NIDDK NIH HHS/United States ; DK073681/DK/NIDDK NIH HHS/United States ; DK61659/DK/NIDDK NIH HHS/United States ; DP-05-069/DP/NCCDPHP CDC HHS/United States ; DP-10-001/DP/NCCDPHP CDC HHS/United States ; NIH P30 DK57516/DK/NIDDK NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; R01 DK061659/DK/NIDDK NIH HHS/United States ; R01 DK067555/DK/NIDDK NIH HHS/United States ; R01 DK073681/DK/NIDDK NIH HHS/United States ; U01 DP000244/DP/NCCDPHP CDC HHS/United States ; U01 DP000245/DP/NCCDPHP CDC HHS/United States ; U01 DP000246/DP/NCCDPHP CDC HHS/United States ; U01 DP000247/DP/NCCDPHP CDC HHS/United States ; U01 DP000248/DP/NCCDPHP CDC HHS/United States ; U01 DP000254/DP/NCCDPHP CDC HHS/United States ; U01DP000250/DP/NCCDPHP CDC HHS/United States ; U18DP002708/DP/NCCDPHP CDC HHS/United States ; U18DP002710-01/DP/NCCDPHP CDC HHS/United States ; U18DP002714/DP/NCCDPHP CDC HHS/United States ; U48/CCU419249/PHS HHS/United States ; U48/CCU519239/PHS HHS/United States ; U48/CCU819241E3/PHS HHS/United States ; U48/CCU919219/PHS HHS/United States ; U58/CCU019235-4/PHS HHS/United States ; U58CCU919256/PHS HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; UL1 TR001082/TR/NCATS NIH HHS/United States ; UL1 TR00423/TR/NCATS NIH HHS/United States ; UL1RR029882/RR/NCRR NIH HHS/United States ; UL1TR000154/TR/NCATS NIH HHS/United States
• Volume:
  60
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:aa34380a85735a1a87ef544b77b72eedf7c2d82417cd4dd261cc73b75c6dc06b
• Download URL:
  https://stacks.cdc.gov/view/cdc/32582/cdc_32582_DS1.pdf
• File Type:
  [PDF - 1.28 MB ]