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TOMER
Genetic susceptibility in thyroid autoimmunity.Ban
Y, Tomer Y. [abstract only] "The autoimmune thyroid diseases (AITD) include Graves' disease (GD) which manifests in hyperthyroidism and Hashimoto's thyroiditis (HT), manifesting as hypothyroidism. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens in AITD. Indeed, there is solid epidemiological data to support a strong genetic influence on the etiology of AITD including family and twin studies. Recently, there has been significant progress toward the identification of the AITD susceptibility genes. Several loci (genetic regions) that are linked with AITD have been mapped and in some of these loci putative AITD susceptibility genes have been identified. Some of these loci predispose to a single phenotype (GD or HT), while other loci 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. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg) and it is likely that the final disease phenotype is a result of an interaction between these loci, as well as environmental influences."
Thyrotropin receptor-associated diseases: from adenomata to Graves disease.Davies
TF, Ando T, Lin RY, Tomer Y, Latif R.
"The thyroid-stimulating hormone receptor (TSHR) is a G protein-linked, 7-transmembrane domain (7-TMD) receptor that undergoes complex posttranslational processing unique to this glycoprotein receptor family. Due to its complex structure, TSHR appears to have unstable molecular integrity and a propensity toward over- or underactivity on the basis of point genetic mutations or antibody-induced structural changes. Hence, both germline and somatic mutations, commonly located in the transmembrane regions, may induce constitutive activation of the receptor, resulting in congenital hyperthyroidism or the development of actively secreting thyroid nodules. Similarly, mutations leading to structural alterations may induce constitutive inactivation and congenital hypothyroidism. The TSHR is also a primary antigen in autoimmune thyroid disease, and some TSHR antibodies may activate the receptor, while others inhibit its activation or have no influence on signal transduction at all, depending on how they influence the integrity of the structure. Clinical assays for such antibodies have improved significantly and are a useful addition to the investigative armamentarium. Furthermore, the relative instability of the receptor can result in shedding of the TSHR ectodomain, providing a source of antigen and activating the autoimmune response. However, it may also provide decoys for TSHR antibodies, thus influencing their biological action and clinical effects. This review discusses the role of the TSHR in the physiological and pathological stimulation of the thyroid."
Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes.Golden
B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y.
"CONTEXT: Epidemiological data suggest a common genetic susceptibility to type 1 diabetes (T1D) and autoimmune thyroid disease (AITD). OBJECTIVE: Our objective was to identify the joint susceptibility genes for T1D and AITD. DESIGN: We conducted a family-based linkage and association study. SETTING: The study took place at an academic medical center. PARTICIPANTS: Participants included 55 multiplex families (290 individuals) in which T1D and AITD clustered (T1D-AITD families). MAIN OUTCOME MEASURES: We conducted tests for linkage and family-based associations (transmission disequilibrium test) with four candidate genes: human leukocyte antigen (HLA), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), insulin variable number of tandem repeats (VNTR), and thyroglobulin. RESULTS: Linkage evidence to HLA appeared when subjects with either T1D or AITD were considered affected [maximum LOD score (MLS), 2.2]. The major HLA haplotype contributing to the shared susceptibility was DR3-DQB1*0201, with DR3 conferring most of the shared risk. The CTLA-4 gene showed evidence for linkage only when individuals with both T1D and AITD were considered affected (MLS, 1.7), and the insulin VNTR showed evidence for linkage when individuals with either T1D or AITD were considered affected (MLS, 1.9); i.e. it may contribute to the familial aggregation of T1D and AITD. CONCLUSIONS: The HLA class II locus contributes to the shared risk for T1D and AITD, and the major HLA haplotype contributing to this association is DR3-DQB1*0201. Additional non-HLA loci contribute to the joint susceptibility to T1D and AITD, and two potential candidates include the CTLA-4 and insulin VNTR loci."
Susceptibility genes in thyroid autoimmunity.Ban
Y, Tomer Y. [abstract only]
"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."
Analysis of immune regulatory genes in familial and sporadic Graves' disease.Ban
Y, Concepcion ES, Villanueva R, Greenberg DA, Davies TF, Tomer Y.
"Graves' disease (GD) is seen in apparently sporadic and familial forms. At least two immune regulatory genes are associated with GD, human leukocyte antigen (HLA) and cytotoxic T lymphocyte antigen-4 (CTLA-4). The aim of our study was to examine the contributions of HLA and CTLA-4 to the familial clustering of GD by analyzing them for association with familial and sporadic GD. We analyzed 160 Caucasian GD patients (69 familial and 91 sporadic), and 150 matched controls. Analysis of all GD patients demonstrated significant associations between GD and HLA-DR3 [P = 9.0 x 10(-7); relative risk (RR) = 3.8] and two CTLA-4 single nucleotide polymorphisms (SNPs), A/G(49) SNP (P = 0.03; RR = 1.5), and CT60 SNP (P = 0.03; RR = 1.4). Moreover, there was evidence for joint susceptibility to risk between HLA-DR3 and CTLA-4, giving a combined RR of 5.9. Subset analysis demonstrated no significant difference between the frequencies of HLA-DR3 and the susceptibility alleles of CTLA-4 A/G(49) and CT60 SNPs in the familial and sporadic GD subsets (P > 0.05). These results suggested that HLA-DR3 and CTLA-4 conferred a general increased risk for GD in both the sporadic and familial forms, and that the risk conferred by them was additive. However, HLA-DR3 and CTLA-4 did not have a stronger effect in the familial GD patients, suggesting that additional genes must contribute to the aggregation of GD within families."
The thyroglobulin gene as the first thyroid-specific susceptibility gene for autoimmune thyroid disease.Tomer
Y, Greenberg D. [abstract only]
"Recent linkage and association studies provide evidence for thyroglobulin (Tg) being an autoimmune thyroid disease (AITD) susceptibility gene. The Tg locus has been reported to be linked with AITD in two independent studies, and further analysis demonstrated that markers within the Tg gene were associated with AITD. Furthermore, missense single-nucleotide polymorphisms (SNPs) in the Tg gene were shown to be associated with autoimmune thyroiditis in both mice and humans. If Tg is confirmed as a susceptibility gene for AITD, it could provide a novel therapeutic target."
The contribution of immune regulatory and thyroid specific genes to the etiology of Graves' and Hashimoto's diseases.Ban
Y, Tomer Y. [abstract only]
"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) are 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 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."
Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families.Tomer
Y, Ban Y, Concepcion E, Barbesino G, Villanueva R, Greenberg DA, Davies
TF.
"The autoimmune thyroid diseases (AITDs), comprising Graves disease (GD) and Hashimoto thyroiditis (HT), develop as a result of a complex interaction between predisposing genes and environmental triggers. Previously, we identified six loci that showed evidence for linkage with AITD in a data set of 56 multiplex families. The goals of the present study were to replicate/reject the previously identified loci before fine mapping and sequencing the candidate genes in these regions. We performed a whole-genome linkage study in an expanded data set of 102 multiplex families with AITD (540 individuals), through use of 400 microsatellite markers. Seven loci showed evidence for linkage to AITD. Three loci, on chromosomes 6p, 8q, and 10q, showed evidence for linkage with both GD and HT (maximum multipoint heterogeneity LOD scores [HLOD] 2.0, 3.5, and 4.1, respectively). Three loci showed evidence for linkage with GD: on 7q (HLOD 2.3), 14q (HLOD 2.1), and 20q (LOD 3.3, in a subset of the families). One locus on 12q showed evidence of linkage with HT, giving an HLOD of 3.4. Comparison with the results obtained in the original data set showed that the 20q (GD-2) and 12q (HT-2) loci continued to show evidence for linkage in the expanded data set; the 6p and 14q loci were located within the same region as the previously identified 6p and 14q loci (AITD-1 and GD-1, respectively), but the Xq (GD-3) and 13q (HT-1) loci were not replicated in the expanded data set. These results demonstrated that multiple genes may predispose to GD and HT and that some may be common to both diseases and some are unique. The loci that continue to show evidence for linkage in the expanded data set represent serious candidate regions for gene identification."
The genetics of the autoimmune thyroid diseases.Davies
TF, Greenberg D, Tomer Y. [abstract only]
"AIM: To understand the modern approach to finding the genes responsible for complex diseases when compared to simple Mendelian inheritance. To define the autoimmune thyroid diseases as we now understand them and introduce the concept of disease heterogeneity. To review the evidence for a genetic contribution to autoimmune thyroid disease as opposed to environmental factors and to be aware of new information generated from recent studies concerning the role of HLA, immune modulators, and new loci of interest providing susceptibility to the autoimmune thyroid diseases."
Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases.Tomer
Y, Greenberg DA, Concepcion E, Ban Y, Davies TF.
"The autoimmune thyroid diseases (AITDs) develop as a result of a complex interaction between predisposing genes and non-genetic factors. We have completed a whole genome scan in 56 families which revealed 7 major AITD loci (LOD scores >2), and additional minor loci (LOD scores >1). One of the minor loci was on chromosome 8q24 giving a maximum LOD score (MLS) of 1.8 at marker D8S284. This locus contained the thyroglobulin (Tg) gene which was a strong candidate gene for AITD. Because of this we analyzed the Tg gene region in detail using an expanded dataset of 102 families. The new linkage analysis showed stronger evidence for linkage at the Tg gene locus with an MLS of 3.5 between markers D8S514 and D8S284 (NPL = 2.0). We then proceeded to analyze the Tg gene directly. We identified a new microsatellite inside intron 27 of the Tg gene (designated Tgms2). Tgms2 showed strong evidence for linkage with AITD (MLS = 2.9), further suggesting that the Tg gene was linked to AITD. Association studies comparing 224 Caucasian AITD patients to 134 Caucasian controls showed an association of Tgms2 with AITD (p = 0.05, relative risk [RR] = 1.4). The association was stronger when only the probands from the linked families (n = 32) were used (p = 0.004, RR = 2.3). Transmission disequilibrium test (TDT) analysis also showed an association of Tgms2 with AITD (p = 0.02). We concluded therefore that the Tg gene was a major AITD susceptibility gene because it was both linked and associated with AITD."
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