Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function

Abstract The autoimmune thyroid diseases (AITD) are complex diseases that are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility, in combination with external factors (e.g., dietary iodine), is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been used to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g., human leukocyte antigen, cytotoxic T lymphocyte antigen-4) and thyroid-specific genes (e.g., TSH receptor, thyroglobulin). Most likely these loci interact, and their interactions may influence disease phenotype and severity. It is hoped that in the near future additional AITD susceptibility genes will be identified and the mechanisms by which they induce AITD will be unraveled.

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Susceptibility Genes in Thyroid Autoimmunity

Clinical and Developmental Immunology ◽

10.1080/17402520400008897 ◽

2005 ◽

Vol 12 (1) ◽

pp. 47-58 ◽

Cited By ~ 33

Author(s):

Yoshiyuki Ban ◽

Yaron Tomer

Keyword(s):

Genetic Susceptibility ◽

Thyroid Autoimmunity ◽

Twin Studies ◽

Epidemiological Data ◽

Susceptibility Genes ◽

Autoimmune Response ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Genome Screening ◽

Shared Genetic

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity.

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Genetic Factors of Autoimmune Thyroid Diseases in Japanese

Autoimmune Diseases ◽

10.1155/2012/236981 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Yoshiyuki Ban

Keyword(s):

Genetic Susceptibility ◽

Twin Studies ◽

Epidemiological Data ◽

Susceptibility Genes ◽

Thyroid Diseases ◽

Autoimmune Response ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Genome Screening ◽

Shared Genetic

Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are caused by immune response to self-thyroid antigens and affect approximately 2–5% of the general population. Genetic susceptibility in combination with external factors, such as smoking, viral/bacterial infection, and chemicals, is believed to initiate the autoimmune response against thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITDs. Various techniques have been employed to identify genes contributing to the etiology of AITDs, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked to AITDs, and, in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to GD and HT and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. Known AITD-susceptibility genes are classified into three groups: HLA genes, non-HLA immune-regulatory genes (e.g., CTLA-4, PTPN22, and CD40), and thyroid-specific genes (e.g., TSHR and Tg). In this paper, we will summarize the latest findings on AITD susceptibility genes in Japanese.

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Identification Of New Rare Variants Associated With Familial Autoimmune Thyroid Diseases By Deep Sequencing Of Linked Loci

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab440 ◽

2021 ◽

Author(s):

Cheuk Wun Li ◽

Ravi Sachidanandam ◽

Anitha Jayaprakash ◽

Zhengzi Yi ◽

Weijia Zhang ◽

...

Keyword(s):

Genetic Susceptibility ◽

Deep Sequencing ◽

Rare Variants ◽

Thyroid Autoimmunity ◽

Susceptibility Genes ◽

Thyroid Diseases ◽

Phosphoglycerate Mutase ◽

Inositol Polyphosphate ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid

Abstract Context Genetic risk factors play a major role in the pathoetiology of autoimmune thyroid diseases (AITD). So far, only common risk variants have been identified in AITD susceptibility genes. Recently, rare genetic variants have emerged as important contributors to complex diseases, and we hypothesized that rare variants play a key role in the genetic susceptibility to AITD. Objective To identify new rare variants that are associated with familial AITD. Design We performed deep sequencing of 3 previously mapped AITD-linked loci (10q, 12q, and 14q) in a dataset of 34 families in which AITD clustered (familial AITD). Results We identified 13 rare variants, located in the inositol polyphosphate multikinase (IPMK) gene, that were associated with AITD (i.e. both Graves’ disease [GD] and Hashimoto’s thyroiditis [HT]); two rare variants, within the dihydrolipoamide S-succinyltransferase (DLST) and zinc-finger FYVE domain-containing protein (ZFYVE1) genes, that were associated with GD only; and 3 rare variants, within the phosphoglycerate mutase 1 pseudogene 5 (PGAM1P5), LOC105369879, and methionine aminopeptidase 2 (MetAP2) genes, that were associated with HT only. Conclusion Our study demonstrates that, in addition to common variants, rare variants also contribute to the genetic susceptibility to AITD. We identified new rare variants in 6 AITD susceptibility genes that predispose to familial AITD. Of them three genes, IPMK, ZFYVE1, and MetAP2, are mechanistically involved in immune pathways and have been previously shown to be associated with autoimmunity. These genes predispose to thyroid autoimmunity and may in the future serve as potential therapeutic targets.

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Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves’ Disease and Hashimoto’s Hypothyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa170 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2600-e2608 ◽

Cited By ~ 2

Author(s):

Qian-Yue Zhang ◽

Wei Liu ◽

Lu Li ◽

Wen-Hua Du ◽

Chun-Lin Zuo ◽

...

Keyword(s):

Susceptibility Genes ◽

Graves Disease ◽

Susceptibility Loci ◽

Chinese Han ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Genome Wide ◽

Chinese Cohort ◽

First Time ◽

Genome Wide Significance

Abstract Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. Objects To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. Design In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. Results We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10–8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. Conclusion Our findings suggested that the pathogenesis of HT and GD was different.

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Fetal cell microchimerism: a protective role in autoimmune thyroid diseases

Acta Endocrinologica ◽

10.1530/eje-15-0028 ◽

2015 ◽

Vol 173 (1) ◽

pp. 111-118 ◽

Cited By ~ 9

Author(s):

Valentina Cirello ◽

Roberta Rizzo ◽

Milena Crippa ◽

Irene Campi ◽

Daria Bortolotti ◽

...

Keyword(s):

Human Leukocyte ◽

Protective Role ◽

Systemic Autoimmune Disease ◽

Fetal Cell ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Leukocyte Antigen ◽

Fetal Cells ◽

Maternal Immune System ◽

Polymorphic Pattern

ObjectiveThe physiological persistence of fetal cells in the circulation and tissue of a previously pregnant woman is called fetal cell microchimerism (FCM). It has been hypothesized to play a role in systemic autoimmune disease; however, only limited data are available regarding its role in autoimmune thyroid disease (AITD).DesignCirculating FCM was analyzed in a large series of previously pregnant women with Graves' disease (GD), Hashimoto's thyroiditis (HT), or no disease (healthy controls (HCs)). To exclude the possible bias related to placental factors, the polymorphic pattern of human leukocyte antigen-G (HLA-G) gene, which is known to be involved in the tolerance of fetal cells by the maternal immune system, was investigated.MethodsFCM was evaluated by PCR in the peripheral blood, and the Y chromosome was identified by fluorescencein situhybridization in some GD tissues.HLA-Gpolymorphism typing was assessed by real-time PCR.ResultsFCM was significantly more frequent in HC (63.6%) than in GD (33.3%) or HT (27.8%) women (P=0.0004 andP=0.001 respectively). A quantitative analysis confirmed that circulating male DNA was more abundant in HC than it was in GD or HT. Microchimeric cells were documented in vessels and in thyroid follicles. In neither GD/HT patients nor HC women was theHLA-Gtyping different between FCM-positive and FCM-negative cases.ConclusionThe higher prevalence of FCM in HC as compared to GD and HT patients suggests that it plays a possible protective role in autoimmune thyroid disorders. Placental factors have been excluded as determinants of the differences found. The vascular and tissue localization of microchimeric cells further highlights the ability of those cells to migrate to damaged tissues.

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Immunological Mechanisms of Autoimmune Thyroid Diseases: A Shift in The Traditional TH1/TH2 Paradigm

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences ◽

10.2478/prolas-2019-0012 ◽

2019 ◽

Vol 73 (2) ◽

pp. 67-77

Author(s):

Tatjana Zaķe ◽

Sandra Skuja ◽

Aivars Lejnieks ◽

Valērija Groma ◽

Ilze Konrāde

Keyword(s):

Thyroid Autoimmunity ◽

Treg Cells ◽

Thyroid Diseases ◽

Autoimmune Response ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Th17 Lymphocytes ◽

Immunological Mechanisms ◽

Thyroid Autoantigens ◽

The Impact

Abstract Autoimmune thyroid diseases (AITD) mainly include Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), which are characterised by the presence of circulating antibodies against various thyroid autoantigens and infiltration of the thyroid gland by autoreactive lymphocytes. Despite the significant advancement in the knowledge of AITD pathogenesis in the last decade, the specific immunological mechanisms responsible for development of the disease are not thoroughly understood. Classically, HT has long been considered as a T helper (Th)1-mediated disease, while a Th2-driven autoimmune response is dominant for GD development. However, this classification has changed due to the description of Th17 lymphocytes, which suggested participation of these cells in AITD, particularly HT pathogenesis. Moreover, a shift in the balance between Th17 and T regulatory (Treg) cells has been observed in thyroid autoimmunity. We have observed overexpression of IL-17, the prominent effector cytokine of Th17, within thyroid tissues from HT and GD patients in our studies. The present review will focus on recent data regarding the role of Treg and Th17 lymphocytes in AITD pathogenesis. In addition, the impact and proposed mechanisms of the predominant environmental factors triggering the autoimmune response to the thyroid will be discussed.

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The Relationship Between Human Leukocyte Antigen Class II Genes and Type 1 Diabetes, Autoimmune Thyroid Diseases, and Autoimmune Polyendocrine Syndrome Type 3

HLA and Associated Important Diseases ◽

10.5772/57498 ◽

2014 ◽

Author(s):

Masahito Katahira

Keyword(s):

Human Leukocyte Antigen Class ◽

Human Leukocyte ◽

Syndrome Type ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Leukocyte Antigen ◽

Autoimmune Polyendocrine Syndrome ◽

Type 3 ◽

The Relationship

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Cytotoxic t-lymphocyte Antigen 4 (ctla-4) - 1661 a/g and -658 c/t Gene Polymorphisms in Autoimmune Thyroid Diseases: a Pilot Study

Acta Endocrinologica (Bucharest) ◽

10.4183/aeb.2011.413 ◽

2011 ◽

Vol 7 (3) ◽

pp. 413-423

Author(s):

I Duncea

Keyword(s):

Pilot Study ◽

T Lymphocyte ◽

Gene Polymorphisms ◽

Cytotoxic T Lymphocyte ◽

Thyroid Diseases ◽

Autoimmune Thyroid Diseases ◽

Lymphocyte Antigen ◽

Autoimmune Thyroid

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CTLA-4 polymorphisms (+49 A/G and -318 C/T) are important genetic determinants of AITD susceptibility and predisposition to high levels of thyroid autoantibodies in Polish children - preliminary study.

Acta Biochimica Polonica ◽

10.18388/abp.2013_2034 ◽

2013 ◽

Vol 60 (4) ◽

Cited By ~ 7

Author(s):

Dorota Pastuszak-Lewandoska ◽

Daria Domańska ◽

Magdalena Rudzińska ◽

Artur Bossowski ◽

Anna Kucharska ◽

...

Keyword(s):

T Lymphocyte ◽

Genomic Dna ◽

Genetic Factors ◽

Cytotoxic T Lymphocyte ◽

Graves Disease ◽

Thyroid Autoantibodies ◽

Genetic Determinants ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Preliminary Study

Autoimmune thyroid diseases (AITDs), including Hashimoto' s thyroiditis (HT) and Graves' disease (GD), are related to environmental and genetic factors. We analyzed the association of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene two polymorphisms (+49 A/G, -318 C/T) with HT and GD development in Polish children, and correlated both polymorphisms with the production of thyroid autoantibodies (TPOAb and TgAb). The study involved 49 AITD patients (age 10-19) with HT (n=25) or GD (n=24) and 69 healthy controls. SNP genotyping was performed using genomic DNA and TaqMan® probes. The obtained results indicated that CTLA-4 +49 GG genotype was significantly more frequent in both HT and GD patients, whereas the AA genotype was more common in controls. CTLA-4-318 CT genotype was significantly more frequent in AITD, and the CC genotype more often occurred in controls. Significantly higher median TPOAb and TgAb values were associated with G allele in HT, and with T allele in GD patients. Concluding, both studied polymorphisms seem to be important genetic determinants of the risk of HT and GD, and appear to be associated with a predisposition to high levels of TAbs and clinical AITD. The obtained results give more information on the distribution of the CTLA-4 polymorphism in Polish AITD children, and further support the proposal that the CTLA-4 gene plays an important role in a TAb production.

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