Elsevier

Journal of Autoimmunity

Volume 60, June 2015, Pages 32-39
Journal of Autoimmunity

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

https://doi.org/10.1016/j.jaut.2015.03.006Get rights and content

Highlights

  • Autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D) are genetically associated.

  • We mapped multiple loci predisposing to T1D + AITD using a genome wide approach.

  • Sixteen genes were non-HLA genes located in the MHC locus.

  • We identified GPR103 as a novel susceptibility gene for T1D + AITD.

  • Major pathways predisposing to T1D + AITD included CD40 and CTLA-4 signaling.

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.

Introduction

The most common autoimmune endocrine disorders are type 1 (autoimmune) diabetes (T1D) and autoimmune thyroid diseases (AITD). T1D and AITD are both characterized by T-cell infiltration and production of autoantibodies directed at the target organs (pancreatic islets and thyroid, respectively), resulting in their dysfunction or destruction [1]. Epidemiological data have shown that T1D and AITD frequently occur together in the same family and in the same individual, suggesting a strong shared genetic susceptibility [1]. In different studies, up to 44% of T1D patients were positive for thyroid antibodies (TAb) (thyroid peroxidase [TPO] and/or thyroglobulin [Tg] antibodies) [2], [3]. Similarly, 2.3% of children with AITD have islet cell antibodies compared with 0% of controls [4]. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as one of the variants of autoimmune polyglandular syndrome type 3 (APS3) [5] (since the phenotype of T1D + AITD in the same individual is a known as a variant of APS3 we refer to it as APS3v in this manuscript).

Family studies also support a strong shared genetic susceptibility to T1D and AITD. One of the largest family studies of T1D and AITD in the US [6], [7], showed that among female diabetic probands Hashimoto's thyroiditis (HT) was diagnosed in 54–75% of cases, and among female relatives, the frequency of HT was 22–44%. Two other studies, one from the UK [8] and one from Colombia [9] showed similar results. Thus, epidemiological data support a significant shared genetic susceptibility to T1D and AITD. However, while much has been learned about the genetics of T1D and AITD individually, less is known about the joint genetic etiology of these two diseases.

In view of the strong evidence for shared susceptibility for T1D and AITD we have previously mapped joint susceptibility genes for T1D and AITD using linkage studies in a large cohort of multiplex families in which T1D and AITD clustered. We used both the candidate gene approach [10], [11], and whole genome linkage approach [12]. A striking finding of these studies was that the phenotype of T1D + AITD in the same individual (APS3v) was a unique phenotype with a genetic predisposition distinct from that of T1D or AITD alone [10], [12]. The most significant contribution to T1D + AITD (APS3v) genetic susceptibility came from a sequence variant in HLA-DR [13]. In addition to the HLA class II susceptibility contribution we mapped three non-MHC loci showing evidence for linkage - CTLA-4, PTPN22, and FOXP3 [10], [11], [12]. These genes as well as other genes, such as IL-2α/CD25 and TNFα have been reported by other groups studying APS3v [14]. The aim of the present study was to identify genes unique for APS3v using the robust genome wide association study (GWAS) approach in order to identify novel shared mechanisms and pathways for T1D and AITD.

Section snippets

Study participants

The project was approved by the Icahn School of Medicine Institutional Review Board. SEARCH for Diabetes in the Youth study participants ≥18 years old or a parent/guardian of participants <18 years provided written informed consent for data collection including DNA. We performed a two-stage GWAS using a discovery set and an independent replication set.

Discovery set (Table 1): The discovery set included 346 non-Hispanic White (NHW) patients with T1D who were also confirmed to be positive for TPO

Association analysis in the discovery set

Detailed characteristics of the discovery set are provided in Table 1A, Table 1B. The discovery set included 346 Caucasian (NHW) APS3v patients; of them 216 (62%) were females and 130 (38%) were males resulting in a female to male (F:M) ratio of 1.6:1. This ratio is significantly higher than the reported F:M ratio in T1D which is close to 1.0 [21], but is consistent with the female preponderance of AITD. The control discovery set consisted of 727 North American Caucasians. There were 451 (62%)

Discussion

Organ-specific autoimmune diseases, such as T1D and AITD, share common underlying pathogenetic mechanisms. Indeed, genetic studies have demonstrated the existence of common autoimmunity genes predisposing to several autoimmune diseases [1], [22]. One of the strongest phenotypic associations between two different organ-specific autoimmune diseases is the association between T1D and AITD [1], suggesting a significant shared genetic susceptibility. In the current study we dissected the joint

Acknowledgments

We thank the Human Biological Data Interchange (Philadelphia, PA) for assisting with the recruitment of the replication set. This work was supported in part by grants DK61659, DK067555 & DK073681 from NIH-NIDDK (to YT). This study was also supported in part by the Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai with funding provided by the Andrea and Charles Bronfman Philanthropies.

The SEARCH for Diabetes in Youth Study is indebted to the many

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