Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

on behalf of the SEARCH for Diabetes in Youth Study

Research output: Contribution to journalArticle

35 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)32-39
Number of pages8
JournalJournal of Autoimmunity
Volume60
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Fingerprint

Autoimmune Thyroiditis
Thyroid Diseases
Type 1 Diabetes Mellitus
Autoimmune Diseases
Genome
Genes
B-Lymphocytes
Autoimmune Polyendocrinopathies
Genetic Predisposition to Disease
Cell Cycle
Software
T-Lymphocytes

Keywords

  • Gene
  • Graves' disease
  • Hashimoto's thyroiditis
  • HLA
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. / on behalf of the SEARCH for Diabetes in Youth Study.

In: Journal of Autoimmunity, Vol. 60, 01.06.2015, p. 32-39.

Research output: Contribution to journalArticle

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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-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.",
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