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Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.
J Autoimmun. 2015 Jun; 60:32-9.JA

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.

Authors+Show Affiliations

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.Division of Pediatric Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Thyroid Research Laboratory, Johannes Gutenberg University Medical Center, Mainz, Germany.Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA.Colorado School of Public Health, University of Colorado, Denver, CO, USA.Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA.Kaiser Permanente Southern California, Department of Research and Evaluation, Pasadena, CA, USA.Department of Pediatrics, University of Washington, Seattle, WA, USA.Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH, USA.The Charles Bronfman Institute for Personalized Medicine, Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.The Charles Bronfman Institute for Personalized Medicine, Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Public Health, Neurosciences, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.Thyroid Research Laboratory, Johannes Gutenberg University Medical Center, Mainz, Germany.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

25936594

Citation

Tomer, Yaron, et al. "Genome Wide Identification of New Genes and Pathways in Patients With Both Autoimmune Thyroiditis and Type 1 Diabetes." Journal of Autoimmunity, vol. 60, 2015, pp. 32-9.
Tomer Y, Dolan LM, Kahaly G, et al. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun. 2015;60:32-9.
Tomer, Y., Dolan, L. M., Kahaly, G., Divers, J., D'Agostino, R. B., Imperatore, G., Dabelea, D., Marcovina, S., Black, M. H., Pihoker, C., Hasham, A., Hammerstad, S. S., Greenberg, D. A., Lotay, V., Zhang, W., Monti, M. C., & Matheis, N. (2015). Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. Journal of Autoimmunity, 60, 32-9. https://doi.org/10.1016/j.jaut.2015.03.006
Tomer Y, et al. Genome Wide Identification of New Genes and Pathways in Patients With Both Autoimmune Thyroiditis and Type 1 Diabetes. J Autoimmun. 2015;60:32-9. PubMed PMID: 25936594.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. AU - Tomer,Yaron, AU - Dolan,Lawrence M, AU - Kahaly,George, AU - Divers,Jasmin, AU - D'Agostino,Ralph B,Jr 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, AU - ,, Y1 - 2015/04/27/ PY - 2015/01/13/received PY - 2015/03/27/revised PY - 2015/03/29/accepted PY - 2015/5/5/entrez PY - 2015/5/6/pubmed PY - 2016/3/25/medline KW - Gene KW - Graves' disease KW - HLA KW - Hashimoto's thyroiditis KW - Type 1 diabetes SP - 32 EP - 9 JF - Journal of autoimmunity JO - J. Autoimmun. VL - 60 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. SN - 1095-9157 UR - https://www.unboundmedicine.com/medline/citation/25936594/Genome_wide_identification_of_new_genes_and_pathways_in_patients_with_both_autoimmune_thyroiditis_and_type_1_diabetes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-8411(15)00044-X DB - PRIME DP - Unbound Medicine ER -