Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.
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.
Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA. Electronic address: Yaron.Tomer@mssm.edu.
Yaron
Y
Tomer
Division of Pediatric Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Lawrence M
LM
Dolan
Thyroid Research Laboratory, Johannes Gutenberg University Medical Center, Mainz, Germany.
George
G
Kahaly
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Jasmin
J
Divers
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Ralph B
RB
D'Agostino
Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Giuseppina
G
Imperatore
Colorado School of Public Health, University of Colorado, Denver, CO, USA.
Dana
D
Dabelea
Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA.
Santica
S
Marcovina
Kaiser Permanente Southern California, Department of Research and Evaluation, Pasadena, CA, USA.
Mary Helen
MH
Black
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Catherine
C
Pihoker
Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alia
A
Hasham
Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sara Salehi
SS
Hammerstad
Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
David A
DA
Greenberg
The Charles Bronfman Institute for Personalized Medicine, Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Vaneet
V
Lotay
The Charles Bronfman Institute for Personalized Medicine, Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Weijia
W
Zhang
Department of Public Health, Neurosciences, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.
Maria Cristina
MC
Monti
Thyroid Research Laboratory, Johannes Gutenberg University Medical Center, Mainz, Germany.
Nina
N
Matheis
D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000235:genetics*
D019013:CD40 Antigens; D060908:CTLA-4 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
Gene; Graves' disease; HLA; Hashimoto's thyroiditis; Type 1 diabetes