Thyroid dysfunction alters gene expression of proteins related to iron homeostasis and metabolomics in male rats.

Thyroid hormones (THs) are crucial in bodily functions, while iron is essential for processes like oxygen transport. Specialized proteins maintain iron balance, including ferritin, transferrin, ferroportin, and hepcidin. Research suggests that THs can influence iron homeostasis by affecting mRNA and protein expression, such as ferritin and transferrin. Our study focused on male rats to assess mRNA expression of iron homeostasis-related proteins and metabolomics in thyroid dysfunction. We found altered gene expression across various tissues (liver, duodenum, spleen, and kidney) and identified disrupted metabolite patterns in thyroid dysfunction. These findings highlight tissue-specific effects of thyroid dysfunction on essential iron homeostasis proteins and provide insights into associated metabolic changes. Our research contributes to understanding the intricate interplay between thyroid hormones and iron balance. By unveiling tissue-specific gene expression alterations and metabolic disruptions caused by thyroid dysfunction, our work lays a foundation for future investigations to explore underlying mechanisms and develop targeted strategies for managing iron-related complications in thyroid disorders.

Exploring blood metabolites and thyroid disorders: a bidirectional mendelian randomization study.

Background: Human blood metabolites have demonstrated close associations with thyroid disorders in observational studies. However, it's essential to determine whether these correlations imply causation. Mendelian Randomization (MR) offers a promising approach to investigate these patterns. Aims: The primary aim of our investigation is to establish causality between blood metabolites and three thyroid disorders: TC, GD, and HT. Methods: We employed a two-sample bidirectional MR analysis approach to assess the relationships between 452 blood metabolites and the three aforementioned thyroid disorders. Causal links were estimated using the IVW method, with sensitivity analyses conducted via MR-Egger, Weighted Median, and MR-PRESSO. We assessed potential heterogeneity and pleiotropy using MR-Egger intercept and Cochran's Q statistic. Additionally, we conducted pathway analysis to identify potential metabolic pathways. Results: We found 46 metabolites that showed suggestive associations with thyroid disease risk, especially Aspartate (ORIVW=7.41; 95%CI: 1.51-36.27; PIVW=0.013) and C-glycosyltryptophan (ORIVW=0.04; 95%CI: 0.00-0.29; PIVW=0.001) impacted TC, Kynurenine (ORIVW=2.69; 95%CI: 1.08-6.66; PIVW=0.032) and 4-androsten-3beta,17beta-diol disulfate 2 (ORIVW=0.78; 95%CI: 0.48-0.91; PIVW=0.024) significantly impacted GD, and Alpha-ketoglutarate (ORIVW=46.89; 95%CI: 4.65-473.28; PIVW=0.001) and X-14189-leucylalanine (ORIVW=0.31; 95%CI: 0.15-0.64 PIVW=0.001) significantly impacted HT. We also detected 23 metabolites influenced by TC and GD. Multiple metabolic pathways have been found to be involved in thyroid disease. Conclusion: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical thyroid disorder screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Systemic lupus erythematosus and thyroid disease: a Mendelian randomization study.

OBJECTIVES: To clarify the controversy between systemic lupus erythematosus (SLE) and thyroid disease, our study was designed to determine whether or not thyroid problems are associated with SLE. METHODS: We obtained the IEU GWAS database for summary information on genome-wide association studies (GWAS) of SLE and thyroid disease (hypothyroidism and hyperthyroidism) in people with European ancestry. Three approaches were employed to assess the causal link between SLE and thyroid disease: MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The pleiotropy and heterogeneity were examined using a variety of techniques, including the MR-Egger intercept, the MR-PRESSO approach, and the Cochran's Q test. RESULTS: MR analysis revealed a relationship between SLE and an elevated incidence of hypothyroidism (IVW OR: 1.004, 95% CI: [1.003, 1.005], P = 8.45E-16) and hyperthyroidism (IVW OR: 1.0009, 95% CI: [1.0005, 1.0010], P = 1.30E-5). Neither horizontal pleiotropy nor heterogeneity was detected in the sensitivity analysis. CONCLUSION: Our MR study presents strong evidence demonstrating a link between SLE and an elevated risk of thyroid illness. This could help us learn more about what causes SLE and give people with SLE more thorough thyroid function tests and evaluations. Key points • We did not discover modest heterogeneity and pleiotropy in our study. •The findings of this study indicate that SLE is related to an elevated risk of hypothyroidism and hyperthyroidism.

In silico assessment of mixture toxicity mechanisms involved in the pathogenesis of thyroid diseases: The combination of toxic metal(oid)s and decabrominated diphenyl ether.

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research.

Molecular Mechanisms in Autoimmune Thyroid Disease.

The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto's thyroiditis). Hashimoto's thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases. This review summarizes the most common genetic, epigenetic, and environmental mechanisms involved in autoimmune thyroid disease.

MicroRNAs in autoimmune thyroid diseases and their role as biomarkers.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. They are emerging as potential biomarkers and as therapeutic targets for several diseases including autoimmune thyroid diseases (AITD). They control a wide range of biological phenomena, including immune activation, apoptosis, differentiation and development, proliferation and metabolism. This function makes miRNAs attractive as disease biomarker candidates or even as therapeutic agents. Because of their stability and reproducibility circulating miRNAs have been an interesting area of research in many diseases, and studies describing their role in the immune response and in autoimmune diseases have progressively developed. The mechanisms underlying AITD remain elusive. AITD pathogenesis is characterized by a multifactorial interplay based on the synergy between susceptibility genes and environmental stimulation, together with epigenetic modulation. Understanding the regulatory role of miRNAs could lead to identify potential susceptibility pathways, diagnostic biomarkers and therapeutic targets for this disease. Herein we update our present knowledge on the role of microRNAs in AITD and discuss on their importance as possible diagnostic and prognostic biomarkers in the most prevalent AITDs: Hashimoto's thyroiditis (HT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). This review provides an overview of the state of the art in the pathological roles of microRNAs as well as in possible novel miRNA-based therapeutic approaches in AITD.

Thyroid findings in pediatric and adult patients with PTEN hamartoma tumor syndrome: A retrospective analysis, and literature review.

PURPOSE: PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients. METHODS: A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. RESULTS: We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years. CONCLUSIONS: Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.

Recurrence risk of autoimmune thyroid and endocrine diseases.

BACKGROUND AND OBJECTIVE: The recurrence risk ratio (λ) expresses the risk ratio of index patients' first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature. METHODS: Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings). RESULTS: As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11-21 and 16, 12-19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17-30.69)/17.57 (11.80-24.36) and 13.48 (8.42-20.52)/10.68 (6.76-16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated. CONCLUSION: These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD.

Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity.

Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood. Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions. Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10-89), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10-8). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10-6). Genetically, strong coheritability was observed between thyroid disease and both major depressive (rg = 0.17, p = 2.7 × 10-4) and ANXs (rg = 0.17, p = 6.7 × 10-6). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 (p < 10-5), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders. Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.

The Use of Tissue-on-Chip Technology to Focus the Search for Extracellular Vesicle miRNA Biomarkers in Thyroid Disease.

Small extracellular vesicles (sEVs) contain microRNAs (miRNAs) which have potential to act as disease-specific biomarkers. The current study uses an established method to maintain human thyroid tissue ex vivo on a tissue-on-chip device, allowing the collection, isolation and interrogation of the sEVs released directly from thyroid tissue. sEVs were analysed for differences in miRNA levels released from benign thyroid tissue, Graves' disease tissue and papillary thyroid cancer (PTC), using miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to identify potential biomarkers of disease. Thyroid biopsies from patients with benign tissue (n = 5), Graves' disease (n = 5) and PTC (n = 5) were perfused with medium containing sEV-depleted serum for 6 days on the tissue-on-chip device. During incubation, the effluents were collected and ultracentrifuged to isolate sEVs; miRNA was extracted and sequenced (miRNASeq). Out of the 15 samples, 14 passed the quality control and miRNASeq analysis detected significantly higher expression of miR-375-3p, miR-7-5p, miR-382-5p and miR-127-3p in the sEVs isolated from Graves' tissue compared to those from benign tissue (false discovery rate; FDR p < 0.05). Similarly, miR-375-3p and miR-7-5p were also detected at a higher level in the Graves' tissue sEVs compared to the PTC tissue sEVs (FDR p < 0.05). No significant differences were observed between miRNA in sEVs from PTC vs. those from benign tissue. These results were supported by Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The novel findings demonstrate that the tissue-on-chip technology is a robust method for isolating sEVs directly from the tissue of interest, which has permitted the identification of four miRNAs, with which further investigation could be used as biomarkers or therapeutic targets within thyroid disease.

Zebrafish as an emerging tool for drug discovery and development for thyroid diseases.

Zebrafish is a useful model for understanding human genetics and diseases and has evolved into a prominent scientific research model. The genetic structure of zebrafish is 70% identical to that of humans. Its small size, low cost, and transparent embryo make it a valuable tool in experimentation. Zebrafish and mammals possess the same molecular mechanism of thyroid organogenesis and development. Thus, thyroid hormone signaling, embryonic development, thyroid-related disorders, and novel genes involved in early thyroid development can all be studied using zebrafish as a model. Here in this review, we emphasize the evolving role of zebrafish as a possible tool for studying the thyroid gland in the context of physiology and pathology. The transcription factors nkx2.1a, pax2a, and hhex which contribute a pivotal role in the differentiation of thyroid primordium are discussed. Further, we have described the role of zebrafish as a model for thyroid cancer, evaluation of defects in thyroid hormone transport, thyroid hormone (TH) metabolism, and as a screening tool to study thyrotoxins. Hence, the present review highlights the role of zebrafish as a novel approach to understand thyroid development and organogenesis.

Association Between Polymorphisms of IL-23/IL-17 Pathway and Clinical Phenotypes of Autoimmune Thyroid Diseases.

BACKGROUND: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD. OBJECTIVES: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci. METHODS: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method. RESULTS: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis. CONCLUSIONS: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Polymorphisms of ATG5 Gene Are Associated with Autoimmune Thyroid Diseases, Especially Thyroid Eye Disease.

Objective: To explore the association of ATG5 gene polymorphisms with autoimmune thyroid diseases (AITDs) including Hashimoto's thyroiditis (HT) and Graves' illness (GD) as well as their clinical features. Methods: rs6568431, rs548234, and rs6937876 were selected to investigate the correlation of single-nucleotide polymorphisms of ATG5 gene with AITDs. Their frequencies in 824 AITD patients, including 271 HT patients and 553 GD patients, and 764 healthy controls were tested using both ligase detection reaction and multiplex polymerase chain reaction. Results: Allele A frequency of rs6568431 in AITDs patients (p = 0.016, OR = 1.201, 95% CI = 1.034 - 1.394) and allele G frequency of rs6937876 in AITDs patients (p = 0.009, OR = 1.223, 95% CI = 1.052 - 1.422) and in GD patients (p = 0.009, OR = 1.247, 95% CI = 1.056 - 1.473) were significantly higher than those in the healthy controls. The frequency of G allele (p = 5.42E - 18, OR = 0.242, 95% CI = 0.173 - 0.339) of rs6937876 was significantly higher in GD patients with ophthalmopathy. However, no relationship was found between family history, age onset, and the three SNPs. Conclusion: The study is the first to reveal the association between AITDs and ATG5 polymorphisms, and ATG5 gene is considered as a predisposing gene to AITDs, especially GDs.

Cytogenetic Patterns, Congenital Heart Disease, and Thyroid Dysfunction in Children with Down Syndrome.

OBJECTIVES: To study the cytogenetic patterns, congenital heart disease, and thyroid dysfunction in children with Down syndrome. STUDY DESIGN: This was a retrospective observational study of children with Down syndrome over a period of 20 years, from a major referral institution in Kerala state, South India. The cytogenetic patterns, echocardiography reports, and thyroid profiles were analyzed using SPSS, version 20, software. The prevalence of heart disease and thyroid status in the various cytogenetic patterns also were analyzed. RESULTS: The prevalence of translocation (9.45%) was high compared with the reported 4% in the literature. More of the younger mothers had translocation with a greater, but not statically significant, incidence of heart disease. Mosaic karotypes (3.04%) were also greater than reported (1%) in the literature, with female preponderance. Heart disease was seen in 58% of cases, with atrial septal defect being the most common lesion, compared with atrioventricular septal defect noted in literature. Hypothyroidism was noted in 31.2% with no difference among the cytogenetic groups. There was no case of hyperthyroidism. CONCLUSIONS: The high prevalence of translocation and mosaic Down syndrome stresses the need for routine karyotyping in children with Down syndrome. The need for routine screening and regular follow up of heart diseases and thyroid status should be emphasized.

The emerging role of transcription factor FOXP3 in thyroid cancer.

Transcription factor FOXP3 is a crucial regulator in the development and function of regulatory T cells (Treg) that are essential for immunological tolerance and homeostasis. Numerous studies have indicated the correlation of tumor infiltrating FOXP3+ Treg upregulation with poor prognostic parameters in thyroid cancer, including lymph node metastases, extrathyroidal extension, and multifocality. Most immune-checkpoint molecules are expressed in Treg. The blockage of such signals with checkpoint inhibitors has been approved for several solid tumors, but not yet for thyroid cancer. Thyroid abnormalities may be induced by checkpoint inhibitors. For example, hypothyroidism, thyrotoxicosis, painless thyroiditis, or even thyroid storm are more frequently associated with anti-PD-1 antibodies (pembrolizumab and nivolumab). Therefore, Targeting FOXP3+ Treg may have impacts on checkpoint molecules and the growth of thyroid cancer. Several factors may impact the role and stability of FOXP3, such as alternative RNA splicing, mutations, and post-translational modification. In addition, the role of FOXP3+ Treg in the tumor microenvironment is also affected by the complex regulatory network formed by FOXP3 and its transcriptional partners. Here we discussed how the expression and function of FOXP3 were regulated and how FOXP3 interacted with its targets in Treg, aiming to help the development of FOXP3 as a potential therapeutic target for thyroid cancer.