HLA-A2 Phenotype may be Protective Against Graves’ Disease but not Against Hashimoto’s Thyroiditis in Caucasians

Bernecker, C.; Ostapczuk, Martin; Vordenbäumen, Stefan; Ehlers, Margret; Thiel, Anne; Schinner, Sven; Willenberg, HS; Scherbaum, W. A.; Schott, M.

doi:10.1055/s-0032-1323704

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Class I genes encode for HLA antigens A, B, and C, class II genes encode for α- and β-chains of the heterodimeric HLA class II antigens DR, DP and DQ. Class III genes encode for complement components ( 63 ).…”

Section: The Genetic Linkmentioning

confidence: 99%

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

Frommer

Kahaly

2021

Front. Endocrinol.

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Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and DQ8 (DQA1*0301-DQB1*0302), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as the cytotoxic T-lymphocyte- associated antigen (CTLA4), the protein tyrosine phosphatase non-receptor type 22 (PTPN22), the interleukin-2 Receptor (IL2Ra), the Vitamin D receptor (VDR), and the tumor-necrosis-factor-α (TNF) that are involved in immune regulation have been identified to confer susceptibility to both T1D and AITD. Other genes including cluster of differentiation 40 (CD40), the forkhead box P3 (FOXP3), the MHC Class I Polypeptide-Related Sequence A (MICA), insulin variable number of tandem repeats (INS-VNTR), the C-Type Lectin Domain Containing 16A (CLEC16A), the Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3) gene, the interferon-induced helicase C domain-containing protein 1 (IFIH1), and various cytokine genes are also under suspicion to increase susceptibility to T1D and AITD. Further, BTB domain and CNC homolog 2 (BACH2), C-C motif chemokine receptor 5 (CCR5), SH2B adaptor protein 3 (SH2B3), and Rac family small GTPase 2 (RAC2) are found to be associated with T1D and AITD by various independent genome wide association studies and overlap in our list, indicating a strong common genetic link for T1D and AITD. As several susceptibility genes and environmental factors contribute to the disease aetiology of both T1D and AITD and/or AP subtype III variant (T1D+AITD) simultaneously, all patients with T1D should be screened for AITD, and vice versa.

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Section: The Genetic Linkmentioning

confidence: 99%

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

Frommer

Kahaly

2021

Front. Endocrinol.

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“…Furthermore, it was estimated that approximately 58% of patients with HT carried at least one of four HLA class I alleles ( HLA - A*02:07 , B*35:01 , B*40:02 , or B*40:06 ) ( 169 ). Conversely, in Caucasian populations, only a few studies have suggested associations between HLA class I alleles and HT risk ( 171 , 172 ). Hence, it is hypothesized that ethnic differences may play a role in the immunological mechanisms involved in thyrocyte destruction ( 169 ).…”

Section: Autoimmune Thyroid Diseasementioning

confidence: 99%

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis: How Far Is Our Understanding?

Żeber‐Lubecka

Hennig

2021

Front. Immunol.

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Polycystic ovary syndrome (PCOS) and Hashimoto’s thyroiditis (HT) are endocrine disorders that commonly occur among young women. A higher prevalence of HT in women with PCOS, relative to healthy individuals, is observed consistently. Combined occurrence of both diseases is associated with a higher risk of severe metabolic and reproductive complications. Genetic factors strongly impact the pathogenesis of both PCOS and HT and several susceptibility loci associated with a higher risk of both disorders have been identified. Furthermore, some candidate gene polymorphisms are thought to be functionally relevant; however, few genetic variants are proposed to be causally associated with the incidence of both disorders together.

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“…An interaction with a SNP in exon 33 of TG has been postulated, suggesting that HLA-DRβ-Arg74 synergises with the disease-associated TG Trp1980Arg SNP [30]. Interestingly, the association of HLA-DRβ-Arg74 is not unique to GD and it may be acting as a general autoimmunity susceptibility allele [31]. The linkage disequilibrium (LD) between genes at the HLA class I and II loci hinder the identification of independent associations Gene expression and SNP data at this locus currently suggest that association may be due to RNASET2, which is expressed in CD4 + T-helper and CD8 + T cells…”

Section: Reviewmentioning

confidence: 99%

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

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As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.

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HLA-A2 Phenotype may be Protective Against Graves’ Disease but not Against Hashimoto’s Thyroiditis in Caucasians

Cited by 9 publications

References 20 publications

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis: How Far Is Our Understanding?

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

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