© Borgis - Postępy Nauk Medycznych 11/2011, s. 969-979
*Ewa Brzeziańska, Aleksandra Gładyś, Daria Domańska
Genetic and epigenetic factors in etiopathology of AITD: molecular and clinical implications
Czynniki genetyczne i epigenetyczne w etiopatogenezie AITD: znaczenie molekularne oraz kliniczne
Department of Molecular Bases of Medicine, Medical University of Lodz, Poland
Head of Department: prof. dr hab. med. Ewa Brzeziańska
W rozwoju autoimmunologicznych chorób tarczycy znaczącą rolę odgrywają interakcje pomiędzy genami, czynnikami środowiskowymi a zmianami epigenetycznymi. W naszej pracy przeglądowej skupiamy się przede wszystkim na czynnikach genetycznych predysponujących do rozwoju choroby Hashimoto oraz choroby Gravesa-Basedowa, zwłaszcza genów zaangażowanych w procesy odpowiedzi immunologicznej: HLA, CTLA-4, CD40, FOXP3, PTPN-22 oraz genów STAT. Epigenetyczna regulacja regionu Xq21-22 oraz Xp11, poprzez metylację promotora może być istotnym mechanizmem zaangażowanym w rozwój AITD. Badania genów immunoregulatorowych udowodniły znaczącą rolę polimorfizmów genów oraz korelacji genotyp-fenotyp w AITD, natomiast regulacja epigenetyczna AITD nie jest dokładnie poznana.
Autoimmune thyroid diseases (AITDs) are caused by interactions between many genes, environmental factors as well as epigenetic modifications. In present review we focus on genetic background of AITD, mainly on genetic predisposition in hyperthyroid Graves’ disease (GD) and Hashimoto’s (goitrous) thyroiditis, including genes affecting the immune response, mainly genes coding human leukocyte antigens (HLA), cytotoxic T-lymphocyte antigen (CTLA-4), CD40, FOXP3, protein tyrosine phosphatase (PTPN-22), as well as STAT proteins. We point out the possible role of epigenetic regulation mechanism via gene promoter methylation in Xq21-22 and Xp11 regions in AITD development. The importance of studies focused on functional polymorphism variants of immunoregulatory genes, genotype-phenotype correlations, as well as not completely yet recognized epigenetic regulation have also been underlined.
Autoimmune thyroid diseases (AITDs), which include hyperthyroid Graves’ disease (GD), Hashimoto’s (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis (PPT), thyroid-associated orbitopathy (TAO), drug-induced thyroiditis, such as interferon-induced thyroiditis, thyroiditis associated with polyglandural autoimmune syndromes and the presence of thyroid antibodies (Tabs) with no apparent clinical disease, are recognized as multifactorial diseases with vital genetic background. The interaction between environmental and genetic factors cause the impairment of self-tolerance to thyroid autoantigens – cellular and humoral immune responses – directed against the thyroid gland due to AITD developing in genetically predisposed individuals. The twin studies and familial aggregation studies have shown the polygenic basis in Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), the most common endocrine disorders in childhood and adolescence. Both diseases are characterized by the presence of thyroid-reactive T cells and infiltration of the thyroid gland. In GD, the majority of T cells undergo a Th2 differentiation and activate B cells to produce TSH receptor (TSHR) antibodies which stimulate the thyroid resulting in clinical hyperthyroidism. In contrast, HT involves Th1 switching of the thyroid infiltrating T cells which induces apoptosis of thyroid follicular cells and clinical hypothyroidism (1).
In recent years the genetic factors as well as epigenetic background of AITD, particularly GD and HT, have been significantly recognized. Especially, immune regulatory genes affecting the immune response, such as genes for human leukocyte antigens (HLA), cytotoxic T-lymphocyte antigen (CTLA-4), CD40, FOXP3, protein tyrosine phosphatase (PTPN-22), TSHR as well as genes for signal transducer and activator of transcription proteins (STATs) are acknowledged as predisposing to AITD (fig. 1) (2).
Figure 1. The chromosome localization of main identified AITD susceptibility genes.
Moreover, the epigenetic mechanism is also observed in pathogenesis of autoimmune diseases. The recent study has shown that X chromosome inactivation (XCI) via DNA methylation, may be involved in AITD development, thus explaining the female-predominant tendency (3).
The genetic factors involved in the onset of AITD
Genes for human major histocompatibility complex (MHC)
The MHC region is recognized as a large genomic area that encodes MHC molecules which play an important role in the immune system and autoimmunity. MHC genomic region consists of a complex of genes located on chromosome 6p21. The genes for MHC molecules are divided into 3 regions: (1) Class I genes encode the HLA antigens A, B, and C, (2) Class II genes encode the heterodimeric HLA-DR, DP, and DQ molecules and (3) Class III genes include genes for: complement components (e.g. C4), tumor necrosis factor alpha (TNFα), heat shock protein 70 (Hsp70), and several other genes. The MHC class II molecules are responsible for the initiation of adaptive immune responses. It has been documented that T-cells recognize and respond to antigens when they are attached to the binding groove of an HLA class II molecule (mostly DR and DQ) on the surface of antigen presenting cell. HLA region is highly polymorphic and contains several other immunoregulatory genes, therefore it has been acknowledged as a pivotal candidate locus for AITD as well as for other autoimmune diseases. Additionally, HLA region is recognized as an important chain of immunological synapse involving peptide antigen bound to HLA molecule, T cell receptor, co-stimulatory molecules, receptors on APCs, as well as integrins (4).
Association of HLA with Graves’ disease
Initial studies based on transmission disequilibrium test (TDT) approach, conducted in a large cohort of GD families, have demonstrated strong linkage between GD and HLA. In another studies focused on the role of HMC area in AITD, tough GD association with HLA-DR3(HLA-DRB1*03) has been found. However, in a study from UK only weak evidence for linkage between GD and the HLA region has been recognized, and another study has reported linkage only when conditioning on DR3. Moreover, it has been documented that HLA-B8 and HLA-DQA1*0501 seems to be crucial in GD in Caucasians (5), Additionally, there are reports demonstrating the role of HLA polymorphisms in the clinical manifestation of GD. Interestingly, some studies have documented an association between the likelihood of relapse of GD and HLA-DR3 (5). The increased frequency of HLA-DR3 in patients with Graves’ ophthalmopathy has been observed, but it has not been confirmed by others.
Association of HLA with Hashimoto’s thyroiditis
The association between HLA haplotypes and HT is less definitive than in GD. Early studies failed to find an association between goitrous HT and HLA A- B- or C-antigens. Subsequently, the association of goitrous HT with HLA-DR5 and of atrophic HT with DR3 has been shown (6). The weak association of HT with HLA-DR4 (6) and DR3 (7) in Caucasians was reported in later studies. This observation has been earlier suggested by the studies on animal model in transgenic mice. Finally, HLA-DQW7 (DQB1*0301) was also reported to be associated with HT in Caucasians (8).
Detailed analysis of the HLA class II locus demonstrated that the major HLA haplotype contributing to the shared susceptibility to T1D and AITD was DR3-DQB1*0201, with DR3 conferring most of the shared risk (9).
The effect of ethnicity on the association of HLA with AITD
Many studies have documented that susceptibility of HLA loci to AITD varies among populations, and no consensus has been obtained. In non-Caucasian population HLA alleles were different from those observed in Caucasian groups. Strong association of HLA-DR3 with AITD was observed in Caucasians while in Asian population (for example in Japanese) the associations between HLA-B35 and GD have been found. One study has reported that HLA-DR3, the primary HLA class II allele, predisposes to the joint susceptibility for T1D and AITDs in families in which both diseases cluster. Moreover, a significant association between DRB1*03 and early onset of polyglandular failure has been found, therefore a cooperative susceptibility genes for AITD and other autoimmune diseases have been confirmed (10).
Moreover, an increased frequency of HLA-BW46 has been reported in Chinese population. However, other class I and II HLA alleles have also been reported to be increased in Asian GD patients. The increased frequency of HLA-DRB3*0202 has been observed in African-Americans (11). Interestingly, one study of a mixed population in Brazil demonstrated an association with HLA-DR3, frequent in European group, indicating that this allele may predispose to AITD in different ethnic groups (12). Alternatively, this Brazilian population may have been comprised mostly of European ancestry.
However, two recent genomewide scans in AITD have failed to detect linkage at 6p21 markers (13). On the other hand, whole-genome linkage screening performed by testing a panel of linkage markers of HLA in AITD, has identified the AITD susceptibility gene on: 2q, 6p (HLA), 8q, 10q, 12q,14q and 20q (4).
Reassuming, the available data suggest that HLA involves immune regulatory genes modulating the gene for AITD but not a primary susceptibility gene.
Functional effects of HLA polymorphism
HLA class II molecules are heterodimeric molecules consisting of α and β chain, which form functional highly polymorphic peptide binding pocket (14). In several autoimmune diseases, including AITD, this specific pocket amino acid sequence is recognized as associated with diseases. Moreover, the specific HLA-DR pocket variants have recently been identified as vital for the development of Graves’ disease (GD) (15) and Hashimoto’s thyroiditis (HT).
Sequencing of HLA-DQ genes have documented that arginine at position 74 of the DRβ1 chain is a critical shared amino acid for the development of both GD and HT (15). It has been claimed that a molecular marker of the HLA-DR pocket, determined by specific amino acids, confers a significant risk for the development of AITD as well as T1D – higher than the risk involving the susceptibility genes. The haplotype consisting of HLA-DR pocket amino acids Tyr-26, Leu-67, Lys-71, and Arg-74 has appeared to be strongly associated with AITD and T1D, while amino acids: Leu-26, Phe-26, Ile-67, Asp-70, Glu-71, Ala-71, and Gln-74 have been recognized as protective. Especially, arginine at position 74 of HLA-DRB1 (DRB1-Arg-74), has been shown to be the pivotal in the development of HT and GD (15). Further analysis has shown that the presence of glutamine at position 74 is protective for GD (15). According to functional mechanism of HLA polymorphism, it is hypothesized that the presence of HLA-DR allele with the appropriate amino acids peptide binding pocket, determines the binding of an autoantigenic thyroidal peptide (16). It is recognized that in pocket 4 (P4) of the DR peptide there is a cleft with position 74 of the DRb1chain. Thus, there is a real possibility that an arginine at position 74 changes the structure of the pocket and therefore has an influence on peptide binding and presentation to T-cells. Indeed, structural modeling analysis has shown that the alteration at position 74, from the common neutral amino acids (Ala or Gln) to a positively charged basic amino acid (Arg), significantly converts the three dimensional structure of the P4 peptide binding pocket. This could modify the peptide binding properties of the DR pocket during presentation to T-cells and favor antigenic peptides that induce GD (15). However, this hypothesis awaits confirmation as very few studies have examined the process of binding and presentation of thyroidal autoantigens to T-cells by different HLA-DR subtypes. Interestingly, the results of Hodge et al. (18) study have suggested the interaction at the genetic level between thyroglobulin gene variant and DRB1-Arg74 predisposing to GD. This observation indicates that the thyroglobulin/DRB1-Arg74 genetic interaction is revealed in biochemical relations, in which Arg74 implicates the presentation of thyroglobulin peptides in the initiation phase of GD. Similarly, the recent studies have identified a pocket HLA-DR amino acid signature that presents strong risk for HT.
Cytotoxic T-lymphocyte-associated protein 4 gene (CTLA-4)
The CTLA-4 gene, located on chromosome 2q33, encodes immunoregulatory molecule, expressed on the surface of activated T cells, which via interaction with B7 molecule downregulates immune functions mediated by T-cells activation (19). It is known that T-cells are activated by APCs that present to the T-cell receptor (TCR ) an antigenic peptide bound to an HLA class II protein on the cell surface. However, a second signal is needed for full T-cell activation, including co-stimulatory signals provided by the APCs themselves or other local cells. The CTLA-4 molecule following activation of the TCR is able to transmit signal in response to its ligation with either B7-1 or B7-2 through competition with CD28.
Human CTLA-4 gene is postulated as a major negative regulator of T-cell activity and important genetic factor responsible for susceptibility to variety of autoimmune diseases (20), including: type 1 diabetes mellitus (T1D) (21), asthma (22), Addison’s disease, myasthenia gravis, Sjogren’s syndrome (23), systemic lupus erythematosus (SLE) (24), systemic sclerosis (25), ulcerative colitis (26) and all forms of AITD (GD, HT, as well as the production of thyroid antibodies TAbs) (27).
CTLA-4 gene is highly polymorphic, that has been confirmed in many linkage and association studies in various autoimmune disorders:
1) A to G SNP substitution (49 A/G) at position 49 in exon 1 CTLA-4, resulting in threonine to alanine substitution at codon 17;
2) C to T SNP substitution in the promoter region at position _318 relative to exon 1 start site (_318 C/T);
3) microsatellite polymorphism CTLA-4(AT)n, which is a dinucleotide (AT) repeat in the 3’UTR of the CTLA-4 gene
4) A to G SNP located downstream and outside of the 3’UTR of the CTLA-4 gene (designated CT60).
Recently, it has been claimed that T-effectors activity could be determined by CTLA-4 SNPs. Especially, A49G dimorphism (Thr/Ala exchange in a peptide) leads to the expression of defective receptor, resulting in the inhibitory effect of CTLA-4 molecule on lymphocyte T-cell (28).
The association between AITDs (HT and/or GD) and CTLA-4 polymorphisms (A49G, 1822 C/T and CT60 A/G) and some other polymorphic sites has been confirmed in several studies. Microsatellite polymorphism CTLA-4(AT)n in 3’UTR region has been reported as a first one associated with autoimmune conditions and consistent in different populations (27). In some studies it has been underlined that CTLA-4(AT)n in 3’UTR region is the most powerful polymorphism associated with GD (27). However, particularly CTLA-4 A49G and CT60 polymorphisms have been correlated with susceptibility to AITD development (29). These associations have been consistent irrespective of ethnic backgrounds, and have been found characteristic in many European as well as Asian populations (30).
Functional effects of CTLA-4 polymorphism
Among the all known polymorphism, A/G49 SNP that substitutes threonine for alanine in the signal peptide, leads to misprocessing of CTLA-4 in the ER, resulting in less efficient glycosylation and diminished surface expression of CTLA-4 protein (31). Other reports bring evidence for association between G allele and reduced control of T-cell proliferation (27). It is claimed that this association may be involved in direct effect of the A/G49 SNP or another polymorphism in linkage disequilibrium with the A/G49 SNP. However, the functional studies have revealed that there are no difference in CTLA-4 expression and/or function in case of transiently transfected T-cell line with endogenous CTLA-4 (Jurkat cells), containing a CTLA-4 construct harboring either G or A allele of the A/G49 SNP (32). This observation has suggested that A/G49 is not the causative SNP, but rather remains in linkage disequlibrium with the causative variant.
The results of association studies, focused on C/T_318 SNP of CTLA-4, are also controversial. The study of have confirmed the association of C/T_318 haplotype with CTLA-4 activity, while the results of have been contrary. Recently performed analysis of C/T_318 SNP have established that T allele is related with higher promoter activity in comparison to C allele (33). It has been accepted that the presence of T allele is associated with significantly enhanced expression of CTLA-4 on the surface of stimulated cells, and significantly increased CTLA-4 mRNA level in resting cells (34). Thus, mechanistically, the C/T_318 SNP may influence CTLA-4 levels by changing the binding of a transcription factor LEF-1 (ang. lymphoid enhancing factor 1), via changing TT(C/T)AAG site, which contains the C/T polymorphism (33).
Moreover, it has been shown that 3’UTR (AT)n is involved in affecting the functions of CTLA. It has been demonstrated that individuals who are carriers of the longer repeated (35). Moreover, the long (AT)n repeats are associated with meaningfully shorter half life of CTLA-4 mRNA in comparison with the short repeats. In addition, the region of CTLA-4 3’UTR in which the (AT)n repeats are located contains three AUUUA motifs which may influence the mRNA stability. Similarly, functional analysis of CT60 SNP in a small group of patients has suggested that the GG genotype (disease susceptible) is associated with the reduced mRNA expression of the soluble form of CTLA-4. In contrast, an association between CT60 genotypes and soluble CTLA-4 mRNA expression levels has not been found in a recently performed large study (36). Regarding the clinical implication of CTLA-4 A/G49 SNP polymorphism, it has been documented that A/G49 in Graves’ disease may be associated with the severity of the initial thyrotoxicosis, mirrored in higher levels of free T4. Moreover, the G allele of this polymorphism has also been found to be associated with the childhood onset of the disease (37). Patients with diagnosed GD and GG genotype of the CTLA-4 A/G49 SNP more often failed to go into remission after five years on anti-thyroid medications (38). In addition, several studies has shown that the development of Graves ophthalmopathy (GO) – usually occuring in a close temporal relationship with hyperthyroidism – may be associated with CTLA-4 A/G49 SNP. On the other hand, the contrary observations have also been reported (39).
It should be stressed that CTLA-4 gene region has been found to be linked with the production of thyroid autoantibodies (TAbs) without clinical manifestations. In another report, an association between G allele of the CTLA-4 A/G49 SNP and thyroid autoantibody diathesis has been documented (40). The G allele of the A/G49 SNP has been also shown to be responsible for higher levels of both thyroglobulin (TgAbs) and thyroid peroxidase autoantibodies (TPOAbs) (41). However, the subsequent studies have recognized that the functional role of CTLA-4 is much more complex than previously suggested. It is foolproof that CTLA-4 may predispose to high levels of Tabs, and at the same time it may eventually lead to the development of clinical AITD. Thus, it has been presumed that CTLA-4 non-specifically plays a role in the susceptibility to thyroid autoimmunity, but the interaction with other loci (e.g., CD40) and/or environmental factors (e.g., iodine) is necessary to the development of a specific AITD phenotype, such as GD.
B cell-associated molecule gene, (CD40)
The CD40 gene, an important regulator of B cell function, is located within the linked region on chromosome 20q11 and, therefore, it is a possible positional candidate gene for GD. CD40 is a 45-50 kDa transmembrane glycoprotein, which is a cell surface receptor expressed on the surface of all mature B cells and most mature B-cell malignancies. The CD40 molecule has been recognized to be expressed predominantly on B cells, and also on monocytes, dendritic cells, epithelial cells and others (42). It is a member of the tumor necrosis factor receptor family of molecules which bind to a ligand (CD40L or CD154), and are expressed mainly on activated T cells. Binding of CD40L to CD40 induces B cells to proliferate and undergo immunoglobulin isotype switching. CD40 posesses a short cytoplasmic tail with no intrinsic enzymatic activity and directly binds the TNFR Associated Factors (TRAFs: TRAF2, TRAF3, TRAF5, and TRAF6). These interactions result in activation of mitogen and stress-activated protein kinase (MAPK/SAPK) cascades, transcription factor activation, cytokine secretion, proliferation, differentiation of B cells into Ig-secreting plasma cells, and the formation of humoral memory (43).
Linkage and association studies have identified CD40 as a susceptibility gene for GD. Interestingly, linkage studies have shown that the CD40 locus was linked and associated with Graves’ disease (44), but not with HT. Sequencing analysis of CD40 gene have documented the presence of C/T polymorphism at 5’UTR, located in the Kozak sequence of CD40, consisted of nucleotides flanking the start ATG codon in vertebrate genes, that is basic to the initiation of translation. Case-control association studies have reported an association between CC genotype and GD (44). This finding has been confirmed in several studies, carried out in different populations, including Caucasian (44), Korean (45), and Japanese (46). On the contrary, the results of some other studies have not confirmed the association between C allele and GD (47). Recently, based on metaanalysis, an association between the CC genotype and GD have been finally demonstrated (48). In addition, persistently high levels of thyroid antibodies after treatment in patients carrying CC genotype have been documented (48).
Functional effects of CD40 polymorphism
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