Genetics of the Autoimmune Polyglandular Syndrome Type 3 Variant

Abstract

Background:

Autoimmune thyroid diseases (AITD) and type 1 diabetes (T1D) are the most common autoimmune endocrine disorders. They occur frequently together in the same individual. This disease combination is denominated as autoimmune polyglandular syndrome type 3 variant (APS3v). This review aims to describe the genetic and pathological background of the syndrome. The joint susceptibility genes for AITD and T1D as well as the underlying pathogenetic mechanisms contributing to the development of autoimmunity are summarized.

Summary:

Family and population studies showed that the APS3v syndrome has a strong genetic background. Whole genome and candidate gene approaches identified several gene variations that are present in both AITD and T1D. Most important common disease susceptibility genes are human leucocyte antigen (chromosome 6), cytotoxic T-lymphocyte–associated antigen 4 (chromosome 2), protein tyrosine phosphatase nonreceptor type 22 (chromosome 1), forkhead box P3 (X chromosome), and the interleukin-2 receptor alpha/CD25 gene region (chromosome 10), all of which contributing to the susceptibility to APS3v. With respect to the underlying pathogenetic mechanisms, these genes are altogether involved in the immune regulation, in particular in the immunological synapse and T-cell activation. In addition to these common genes, there are further candidate genes with joint risk for AITD and T1D, in particular the v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 gene (chromosome 12) and C-type lectin domain family 16 member A gene (chromosome 16). The latter one might be involved in pathogen recognition.

Conclusions:

AITD and T1D share common susceptibility gene variants that possibly act pleiotropically as risk factors for the development of autoimmunity in APS3v. The functional consequences of the genetic variants as well as their interactions should be explored in greater detail. In particular, the functional consequences of the variants of forkhead box P3 predisposing to APS3v need to be elucidated. Finally, further large-scale genome-wide associations studies of single-nucleotide polymorphism variations capturing many thousand individual genetic profiles are warranted to identify further genes that are linked to the etiology of APS3v.

Definition of the Autoimmune Polyglandular Syndrome Type 3 Variant

A utoimmune polyglandular syndromes (APS) comprise autoimmune disorders of a wide spectrum. On the basis of manifestations of disease components, a juvenile type (APS1) and several adult types (APS2 and APS3) are known (1,2). The adult APS2 type is characterized by the presence of autoimmune Addison's disease and either type 1 diabetes (T1D) or autoimmune thyroid disease (AITD), or both (3 –5). The APS3 type is defined as the combination of AITD and other autoimmune diseases except for Addison's disease and hypoparathyroidism (6). Here, the particular disease association between AITD and T1D in the same individual is considered as one variant of APS3, denominated as APS3 variant (APS3v) (7). Hence, diagnostic criteria for APS3v are the clinical association between the overt manifestation of both AITD and T1D in the same subject (see below). Positive family history of endocrine autoimmunity and certain laboratory tests, that is, numerous, highly positive autoantibodies directed against pancreas and thyroid antigens, may predispose to APS3v. Since AITD and T1D are the most common autoimmune endocrine disorders, this review is dedicated to APS3v. There are many data on the susceptibility genes for AITD or T1D, but less data on joint susceptibility genes (8). The objective is to describe the shared susceptibility genes for AITD and T1D as well as to outline the underlying pathogenetic mechanisms that contribute to the development of autoimmunity, as known so far.

Clinical Characteristics, Phenotype, and Prevalence

APS3v is a disorder characterized by autoimmunity relative to the thyroid and the islet cells of the pancreas. It consists of two component diseases of autoimmune genesis but with distinct pathogenesis, AITD and T1D. T1D is caused by autoimmune destruction of insulin-producing β-cells of the pancreas. AITD include Graves' disease (GD), Hashimoto's thyroiditis, or positivity for thyroid autoantibodies. GD is defined by the presence of hyperthyroidism together with the presence of thyrotropin receptor autoantibodies, and HT is defined as primary hypothyroidism, atrophic thyroid gland, and increased level of thyroid peroxidase (TPO) autoantibodies. T1D is characterized by complete insulin deficiency with the presence of least two autoantibodies against the pancreas (glutamate decarboxylase [GAD], tyrosine phosphatase of the β-cell [IA2], and/or islet cell autoantibodies). Both AITD and T1D are organ-specific T-cell-mediated diseases where endocrine glands are affected by autoantibodies. In both disorders, T-cell infiltration occurs with subsequent dysfunction and destruction. Several studies have shown that AITD is frequently combined with T1D in populations of both European and Asian ancestry (9 –11). They occur more often together than would be expected by the population prevalence of each disease (12). Clinical data found that 25% of adolescents with T1D also had thyroid antibodies (13).

Single and Shared Susceptibility Genes

Overview

AITD and T1D are both multifactorial diseases where several susceptibility genes and environmental factors contribute to the disease etiology. Although differences exist in the pathogenesis of both diseases, epidemiological data revealed familial clustering of AITD and T1D. This suggests a common genetic basis for both diseases. This is confirmed by genetic studies showing that some genes confer risk for developing both AITD and T1D. These genes have been denominated as shared or joint susceptibility genes for APS3v. This suggests that the gene product is implicated in the pathogenesis of both AITD and T1D. There is evidence for a common genetic susceptibility for AITD (14) and T1D being responsible for the similar pathogenesis of both disorders (8). Whole-genome linkage screening as well as candidate gene studies have been performed to identify genes contributing to APS3v, thus being common both to AITD and T1D (15 –17). At least four shared susceptibility genes for APS3v with immune regulatory function have been reported so far (Table 1). These are the human leucocyte antigen class II (HLA-DR3) genes on chromosome 6 (13,18 –27), the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) gene on chromosome 2 (28), the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene on chromosome 1 (29,30), and the forkhead box P3 (FOXP3) gene on the X chromosome (17). Interestingly, one of these confirmed genes, CTLA-4, has only a very weak association with T1D as a single disease, but a much stronger association with APSv3 (31). Besides these confirmed joint susceptibility genes for APS3v, there are other genes under discussion to be joint susceptibility genes (Table 1). These are interleukin-2 receptor alpha (IL-2Rα)/CD25, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), C-type lectin domain family 16 member A (CLEC16A), and tumor necrosis factor alpha (TNF-α). The IL-2Rα/CD25 gene region on chromosome 10, which is also involved in immune regulation, has been associated with both AITD and T1D (15). Further candidate genes are the ERBB3 gene on chromosome 12 and the CLEC16A (earlier denominated as KIAA0350) gene on chromosome 16. They have recently been found as common risk factors for AITD and T1D in Japanese (16), but a replication of this finding is needed. Also, the TNF-α gene on chromosome 6 has been reported to be a susceptibility gene for patients showing both AITD and T1D in a European sample (32). Further, there are two additional tissue-specific genes, the insulin (INS) gene variable number of tandem repeat (VNTR) on chromosome 11 in T1D and the thyroglobulin gene on chromosome 8 in AITD, that might be related with APS3v (8,17).

Table 1.

Susceptibility Genes for Autoimmune Polyglandular Syndrome 3 Variant

Gene	Chromosome	Function
Confirmed joint susceptibility genes
HLA class II genes	6	Presents autoantigens to T cells
CTLA-4	2	Suppresses T-cell activation
PTPN22	1	Negatively influences T-cell receptor signaling pathway
FOXP3	X	Controls differentiation of regulatory T cells
Candidate joint susceptibility genes
CLEC16A	16	Could be implicated in pathogen recognition
ERBB3	12	Not defined
IL-2Rα/CD25	10	Plays a role with respect to production and function of regulatory T cells
TNF-α	6	Implicated in pathogenesis of autoimmune diseases
Tg	8	Represents a major target of the immune response in AITD
VNTR (insulin)	11	May alter transcription of the insulin gene

AITD, autoimmune thyroid disease; CLEC16A, C-type lectin domain family 16 member A; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; ERBB3, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3; FOXP3, forkhead box P3; HLA, human leucocyte antigen; IL-2Rα/CD25, interleukin-2 receptor alpha/CD25; PTPN22, protein tyrosine phosphatase nonreceptor type 22; Tg, thyroglobulin; TNF-α, tumor necrosis factor alpha; VNTR (insulin), insulin gene variable number of tandem repeat.

The specific polymorphisms of these genes, being associated with increased risk for APS3v, are summarized.

Specific polymorphisms associated with APS3v:

The HLA class II genes on chromosome 6p21 have been extensively studied in patients with AITD and T1D. Joint susceptibility for AITD and T1D has been demonstrated in both Caucasians and Asians (20 –26). A family linkage study in Caucasians showed that HLA-DR3 is the major HLA allele contributing to the common susceptibility of AITD and T1D (24). HLA-DR3-DQB1*0201 is the major HLA haplotype that confers susceptibility to both AITD and T1D (25). Several population studies suggest that both HLA haplotypes DR3-DQB1*0201 and DR4-DQB1*0302 contribute to the APS3v of combined AITD and T1D (13,20,25,27). The DRB1*0405/DQA1*0301/DQB1*0401 haplotype was reported to be significantly increased in Taiwanese patients with APS3v (22). Early onset of APS3v was found to be associated with HLA-DRB1*03 (27). A study in a large family from Sweden revealed a strong genetic interaction of the HLA and CTLA-4 loci in APS3v (33).

Several studies have shown that the CTLA-4 gene on chromosome 2q33 is a further major susceptibility gene for APS3v, being consistent across different ethnic groups, that is, Caucasians and Asians (25,28,34). A family study found a preferential transmission of the G allele of the CTLA-4 single-nucleotide A/G49 polymorphism in exon 1 to offspring affected by APS3v (17). The G variant showed shared susceptibility for AITD and T1D (35). The A/G49 single-nucleotide polymorphism (SNP) is shared by AITD and T1D in Caucasians and Asians (17,28,36). Further, the CTLA-4 SNP rs3087243 (+6230G >A) showed a significant association with APS3v, in particular referring to patients with T1D and GD (16). The CTLA-4 CT60 GG genotype was significantly increased in patients with APS3v (37).

The PTPN22 gene is located on chromosome 1p13 (38). The minor T allele of an 1858C → T substitution in the PTPN22 gene was observed to be associated with AITD (39), T1D (40), and APS3v (29). Further, a G1123C SNP in the promoter region of the PTPN22 gene has been associated with T1D and AITD in Asians (30).

The FOXP3 gene maps on the p arm of the X chromosome (Xp11.23). The gene has 11 coding exons. A haplotype consisting of allele 10 of the intron 5 microsatellite (TC)n and the T allele of the 3′ untranslated region C/T SNP (rs2294021) was strongly associated with APS3v in Caucasians (17).

IL-2Rα/CD25 gene region: CD25 plays a cardinal role in the development and function of regulatory T cells. The IL-2Rα/CD25 chain is a subunit that makes up the high affinity IL-2R (41). The IL-2Rα/CD25 gene region is located on chromosome 10p15. The CD25 region has been found to be associated with both T1D and AITD (GD) (15).

The ERBB3 gene is located on chromosome 12q13. The SNP rs2292399 in intron 7 of ERBB3 has been shown to be associated with AITD and T1D with the A allele increasing the risk for APS3v (16).

The CLEC16A gene is located on chromosome 16p13. The SNP rs2903692 shows a single-nucleotide G > A polymorphism that was significantly associated with AITD and T1D with the G allele increasing the risk for APS3v (16).

The TNF-α gene is located on chromosome 6p21.3. The A allele of a −308G/A SNP in the promoter region of the gene conferred increased risk for patients having both AITD and T1D, compared with controls (32).

INS VNTR gene: The INS gene region on chromosome 11p5 (IDDM2) maps to a VNTR in the regulatory region of the INS gene. On the basis of the number of the VNTRs, three classes are differentiated. A family study found an association of the insulin VNTR class I alleles with the APS3v phenotype (17). This indicates that the VNTR class I alleles contribute to the susceptibility to the T1D component within the APS3v phenotype. By contrast, another study found no association with AITD (GD) (42). Further studies are needed to elucidate the association of the VNTR with APS3v.

These genes might interact with one another as well as with environmental triggers.

Pathogenetic Mechanisms Contributing to Autoimmunity

AITD and T1D are both organ-specific T-cell-mediated diseases. All four common susceptibility genes identified for APS3v are involved in the immunological synapse and T-cell activation (43): the HLA-DR molecules present autoantigens to T cells, CTLA-4 suppresses T-cell activation, PTPN22 negatively influences the T cell receptor signaling pathway, and FOXP3 regulates the differentiation of regulatory T cells (43) (Fig. 1).

The different HLA class II alleles show different pocket II structures and different affinities for peptides (44). There are two mechanisms under discussion by which HLA class II variants could be involved in a common etiology of AITD and T1D. The first mechanism refers to the structure of the HLA pockets, coded by the HLA class II alleles, and the second mechanism refers to the peptide binding (31,45). First, two distinct HLA class II molecules (e.g., DR3 for AITD and DQB1 for T1D) with distinct pocket structures are in tight linkage disequilibrium and, thereby, are inherited together and expressed on antigen-presenting cells together. Thus, both thyroid-derived peptides and islet cell peptides will fit in these pockets. Second, two distinct HLA class II molecules share a similar HLA class II pocket structure fitting both thyroid-derived peptides as well as islet cell peptides (17). The common pocket structure could also influence the anchoring of the T-cell receptor and not the peptide binding (31,45).

The CTLA - 4 gene encodes a receptor that is expressed on T cells. It is a negative regulator of T-cell activation and downregulates it (31,46). A genetic variant that decreases CTLA-4 function and, therefore, increases T-cell activation might promote development of autoimmunity in APS3v. The A/G49 SNP results in a threonine-to-alanine substitution in the signal peptide of the CTLA-4 protein. This leads to a less efficient glycosylation in the endoplasmatic reticulum and reduced surface expression of the CTLA-4 protein (47). This might affect CTLA-4 function or expression, resulting in increased T-cell activation (17).

The PTPN22 gene encodes the lymphoid tyrosine phosphatase (LYP) that is expressed in immature and mature B and T lymphocytes. This enzyme is a negative regulator of signal transduction through the T-cell receptor, because it inhibits the T lymphocyte antigen receptor signaling pathway (48). The LYP enzyme binds to protein kinase (Csk), thereby limiting the response to antigens (49). A mutation in PTPN22 causing a tryptophan for arginine substitution in the LYP protein (R620W) has been reported to be associated with several autoimmune disorders, including AITD and T1D (49 –52). Considering AITD, the PTPN22 variant was found to be associated with GD as well as with HT (39,53,54), but the association with GD seems to be stronger than with HT.

The FOXP3 gene is an important regulator of differentiation of regulatory T cells (55). A reduced function, due to genetic variants, could promote the development of autoimmunity in APS3v. A haplotype consisting of allele 10 of a microsatellite and the T allele of a C/T SNP was related with APS3v (17). Because the microsatellite is located past the zinc finger domain of the FOXP3 gene, it could affect downstream splicing, thereby impeding the function of the gene (17). Further studies are needed to analyze the functional relevance of the FOXP3 variants that are common in AITD and T1D.

The IL-2Rα/CD25 gene region: CD25 plays an important role with respect to production and function of regulatory T cells, which actively suppress autoreactive T cells in the periphery (56). Therefore, polymorphisms in the CD25 gene region might affect the function of regulatory T cells and, thereby, could influence the development of the autoimmune diseases AITD and T1D (15).

The CLEC16A gene contains a C-type lectin domain, and the encoded protein has been detected in immune cells (57). It could be implicated in pathogen recognition and, therefore, might predispose to immune-mediated diseases.

The TNF-α gene is located within the class III region of the major histocompatibility complex, between HLA-B loci of class I and HLA-D loci of class II. It encodes the proinflammatory cytokine TNF-α. It has been shown that the uncommon A allele of the TNF-α −308 SNP is associated with increased transcription and production of the TNF-α protein, which has been implicated in the pathogenesis of autoimmune diseases (58 –60).

FIG. 1.

The immunological synapse showing the relationship between T cells and antigen presenting cells (APC). Shared susceptibility genes for autoimmune thyroid disease and type 1 diabetes are involved in the immunological synapse. Human leucocyte antigen (HLA)-DR molecules present autoantigens to T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) suppresses T-cell activation, protein tyrosine phosphatase nonreceptor type 22 (PTPN22) negatively influences the T-cell receptor (TCR) signaling pathway, and forkhead box P3 (FOXP3) regulates the differentiation of regulatory T cells (modified after Ref. 43).

Altogether, these findings indicate a similar pathogenesis of AITD and T1D.

Genetic Testing of Persons at Risk

The data support a genetic basis for APSv3. The susceptibility genes described above may not be causative for APS3v, but they increase the risk for developing the disease. Therefore, genetic testing will not identify patients with APS3v, but could identify patients at risk for developing APS3v. Such test should be done on first-degree family members of patients with APS3v, because they show an increased risk for developing autoimmune disorders. Thus, genetic testing would be appropriate in children and siblings of affected persons. Candidate genes for genetic testing are the HLA class II, CTLA-4, PTPN22, and FOXP3 genes. Identification of further joint susceptibility genes for AITD and T1D is necessary in developing genetic testing of family members at risk. To the author's knowledge, at the moment, there are no clinical laboratories available for commercially genetic testing for identifying polymorphisms in genes related to APS3v. Genetic testing is a complex process that needs accurate and reliable laboratory procedures. The interpretation of results of genetic tests in the context of multifactorial diseases with polygenic and environmental components is complex even for trained physicians.

Future Research Directions

From the existing findings, several questions with regard to the genetics of the APS3v phenotype emerge that require further investigation. The common molecular genetic mechanisms related to the association between AITD and T1D should be investigated. Further studies are necessary for elucidating the causal variants with respect to the associations of different SNPs with APS3v. Some gene loci might be generalized susceptibility loci for the development of autoimmune disorders, affecting both the development of AITD and T1D. Work also remains to analyze the functional consequences of the genetic variants. In particular, the functional consequences of the variants of FOXP3 predisposing to APS3v needed to be elucidated in greater detail. In addition, expression analyses as well as protein analyses are necessary. Finally, there is need for further large-scale genome-wide association studies of SNP variations in different ethnic populations capturing many thousand individual genetic profiles to identify further genes that are linked to the etiology of APS3v.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

Portions of this review were presented at the Spring 2010 Meeting of the American Thyroid Association, “Thyroid Disorders in the Era of Personalized Medicine,” Minneapolis, MN, May 13–16, 2010.

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