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Kim W, Seo MK, Kim YJ, Choi SH, Ku CR, Kim S, Lee EJ, Yoon JS. Role of the suppressor of cytokine signaling-3 in the pathogenesis of Graves' orbitopathy. Front Endocrinol (Lausanne) 2025; 16:1527275. [PMID: 40104138 PMCID: PMC11913680 DOI: 10.3389/fendo.2025.1527275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/12/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Graves' orbitopathy (GO) is characterized by increased production of proinflammatory cytokines and hyaluronic acid by fibroblasts and their differentiation into adipocytes in response to immunologic stimuli. The suppressor of cytokine signaling-3 (SOCS3) is an inducible negative regulator of the JAK/STAT pathway, implicated in various inflammatory diseases. In this study, we investigated the role of SOCS3 in the inflammatory and adipogenic pathogenesis of GO. Methods Transcriptome profiling of orbital tissues obtained from five patients with GO who underwent orbital decompression surgery and four healthy subjects was performed using RNA-sequencing. Among the top-ranked differentially expressed genes, we identified 24 hub genes and found SOCS3 to be the most significantly upregulated gene in GO samples compared with that in healthy tissue based on quantitative real-time polymerase chain reaction. SOCS3 expression was analyzed in IL-1β-, and IGF-1-stimulated orbital fibroblasts using quantitative real-time polymerase chain reaction and western blot analysis. Knockdown of SOCS3 using siRNA transfection was performed to assess the effect of SOCS3 on the production of proinflammatory cytokines and adipogenic phenotype. Results We identified 184 consistently differentially expressed genes-120 upregulated and 64 downregulated- in GO tissues compared to the control. SOCS3 mRNA expression was significantly higher in GO tissues (n = 17) compared with that in control (n = 15). IL-1β and IGF-1 enhanced the expression of SOCS3 at mRNA and protein levels. Silencing of SOCS3 suppressed the levels of IL-1β-induced proinflammatory cytokines, including IL-6, IL-8, and ICAM-1. Phosphorylation of NF-kB and Akt was suppressed and adipogenic differentiation was significantly attenuated by SOCS3 knockdown. Conclusions SOCS3 was remarkably expressed in the adipose tissues of patients with GO and was induced by IL-1β and IGF-1 in orbital fibroblasts. SOCS3 inhibition attenuated the production of proinflammatory cytokines and adipogenesis, suggesting that SOCS3 may be a therapeutic target for controlling the inflammatory and adipogenic mechanisms in GO.
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Affiliation(s)
- Wonjin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Republic of Korea
| | - Mi-Kyoung Seo
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Yong Joon Kim
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Hyun Choi
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Cheol Ryong Ku
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sangwoo Kim
- Department of Biochemical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Jig Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Sook Yoon
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Khan S, Rani N, Yadav A, Gupta R. Impact of rs2046045 SNP in PDE8B on TSH Levels: Insights into Genetic Susceptibility to Hypothyroidism. Biochem Genet 2024:10.1007/s10528-024-11005-y. [PMID: 39707102 DOI: 10.1007/s10528-024-11005-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/12/2024] [Indexed: 12/23/2024]
Abstract
Hypothyroidism is the most prevalent thyroid disorder and leads to adverse effects on the human body. Serum thyroid stimulating hormone (TSH) values have been related to polymorphisms in multiple genes that may be involved in the regulation of thyroid function. The single nucleotide polymorphism (SNP) rs2046045 is situated in the intron region of the phosphodiesterase 8B (PDE8B) gene, which encodes a high-affinity cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase widely expressed in thyroid tissue. The principal goal of the present study was to investigate the association between the SNP rs2046045 of the PDE8B gene and hypothyroidism. The study was designed as a case-control study, and a total of 160 hypothyroid and 160 healthy controls were involved. Blood samples were drawn from each individual, and deoxyribonuleic acid (DNA) was separated with a suitable DNA isolation kit. For genotyping, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed. The IBM Statistical Package for Social Sciences (SPSS) 25.0 was utilized to analyze the statistical data. Age differences between the patients and controls were not observed in the present study. The genotype frequency of homozygous wild type (TT), homozygous mutate type (GG), and heterozygous (GT) was 45%, 2.5%, and 52.5%, respectively, in control subjects and 27.5%, 11.25%, and 61.25%, respectively, in cases, and showed a significant difference (p = 0.0002). The minor G allele frequency is elevated in hypothyroid patients as compared to healthy control subjects (41.87% vs. 28.75%), p = 0.0005. The presence of the mutant allele G of rs2046045 in the PDE8B gene correlates with elevated serum TSH levels in hypothyroid patients.
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Affiliation(s)
- Salim Khan
- Department of Biochemistry, Kurukshetra University, Kurukshetra, Haryana, 136119, India
| | - Nikki Rani
- Department of Biochemistry, Kurukshetra University, Kurukshetra, Haryana, 136119, India
| | - Anita Yadav
- Department of Biotechnology, Kurukshetra University, Kurukshetra, Haryana, 136119, India
| | - Ranjan Gupta
- Department of Biochemistry, Kurukshetra University, Kurukshetra, Haryana, 136119, India.
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Marinò M, Rotondo Dottore G, Menconi F, Comi S, Cosentino G, Rocchi R, Latrofa F, Figus M, Santini F. Role of genetics and epigenetics in Graves' orbitopathy. Eur Thyroid J 2024; 13:e240179. [PMID: 39378053 PMCID: PMC11623286 DOI: 10.1530/etj-24-0179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 10/08/2024] [Indexed: 10/10/2024] Open
Abstract
Objectives The pathogenesis of Graves' orbitopathy (GO) remains to be fully elucidated. Here, we reviewed the role of genetics and epigenetics. Design We conducted a PubMed search with the following keywords: GO, thyroid eye disease; or Graves' ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome, and methylome analyses were performed were chosen. Results The different prevalence of GO in the two sexes, as well as racial differences, suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and patient-derived orbital fibroblasts suggests a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated. Conclusions Although no pathogenic gene variants have been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.
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Affiliation(s)
- Michele Marinò
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Giovanna Rotondo Dottore
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Francesca Menconi
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Simone Comi
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Giada Cosentino
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Roberto Rocchi
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Francesco Latrofa
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Michele Figus
- Department of Surgical, Medical and Molecular Pathology, Ophthalmopathy Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy
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Carafone L, Knutson AJ, Gigliotti BJ. A Review of Autoimmune Thyroid Diseases and Their Complex Interplay with Female Fertility. Semin Reprod Med 2024; 42:178-192. [PMID: 39667368 DOI: 10.1055/s-0044-1795160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
Hashimoto thyroiditis and Graves' disease are autoimmune thyroid disorders that are common in women of reproductive age and have a complex relationship with female fertility and health of the maternal-fetal dyad. Both hyperthyroidism and hypothyroidism, whether subclinical or overt in severity, directly or indirectly affect nearly every level of the hypothalamic-pituitary-ovary axis, uterine and ovarian function, as well as fetal development from implantation through delivery. Autoimmunity itself also appears to negatively impact both spontaneous and assisted fertility, as well as miscarriage risk, although the mechanism remains unclear, and the presence and magnitude of risk is variable in published literature. While treatment of overt hyperthyroidism and hypothyroidism is unequivocally recommended by professional societies, the impact of treatment on fertility outcomes, and the role of treatment in subclinical thyroid disease is more controversial. Unfortunately, levothyroxine has not been shown to abrogate the risk of subfertility and miscarriage observed in euthyroid thyroid autoantibody positive women.
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Affiliation(s)
- Lindsay Carafone
- Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York
| | - Alex J Knutson
- Department of Obstetrics & Gynecology, University of Rochester Medical Center, Rochester, New York
| | - Benjamin J Gigliotti
- Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York
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Zhang W, Ding R, Hu Y, Wei W, Tian D, Qin N, Yu H, Wang X. Unraveling susceptibility genes: A contemporary overview of autoimmune thyroid diseases. Int Immunopharmacol 2024; 136:112313. [PMID: 38810306 DOI: 10.1016/j.intimp.2024.112313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/17/2024] [Accepted: 05/19/2024] [Indexed: 05/31/2024]
Abstract
Autoimmune thyroid diseases (AITDs), including Graves' disease and Hashimoto's thyroiditis, are organ-specific autoimmune disorders characterized by conditions including goiter, autoimmune thyroiditis, hyperthyroidism, and hypothyroidism, which represent the most severe clinical manifestations of AITDs. The prevalence of autoimmune thyroid disorders is on the rise, influenced by increased environmental factors and changes in modern lifestyles. Understanding the pathophysiology of AITDs is crucial for identifying key factors that affect the disease's onset, progression, and recurrence, thereby laying a solid foundation for precise diagnosis and treatment. The development of AITDs involves a complex interplay of environmental influences, immune dysfunctions, and genetic predispositions. Genetic predispositions, in particular, are significant, with numerous genes identified as being linked to AITDs. This article focuses on examining the genes vulnerable to AITDs to deepen our understanding of the relevant genetic contributors, ultimately facilitating the development of effective prevention and treatment methods.
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Affiliation(s)
- Wenxin Zhang
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Rong Ding
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuelin Hu
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Wenwen Wei
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Dan Tian
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nalin Qin
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China
| | - Hongsong Yu
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China.
| | - Xin Wang
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou, China.
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Wang R, Lv Y, Dou T, Yang Q, Yu C, Guan Q. Autoimmune thyroid disease and ovarian hypofunction: a review of literature. J Ovarian Res 2024; 17:125. [PMID: 38877588 PMCID: PMC11177435 DOI: 10.1186/s13048-024-01451-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 06/10/2024] [Indexed: 06/16/2024] Open
Abstract
Thyroid hormones(THs) are essential for the proper functioning of the ovaries, and multiple studies have shown that thyroid abnormalities, especially during adolescence and reproductive age, can lead to lifelong ovarian dysfunction. Autoimmune thyroid disease (AITD), one of the most common organ specific autoimmune diseases, is mainly mediated by cellular autoimmune reactions, and has strong inflammatory infiltration and immune active cells, including chemokines and cytokines, which are important components of ovarian aging. This suggests that autoimmune and inflammatory molecular processes may play a role in the emergence of ovarian dysfunction. The purpose of this review is to summarize recent in vivo and in vitro evidence of a complex relationship between AITD and ovarian dysfunction. AITD is closely related to the decline of ovarian function from the perspective of antibody, cytokine, oxidative stress, and genetic factors. Finally, some of the currently known treatments for AITD and hypo ovarian disease are summarized.
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Affiliation(s)
- Ru Wang
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging,Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital of Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
| | - Youyuan Lv
- Internal Medicine Department of the Second Affiliated Hospital of Shandong University, Jinan, 250021, Shandong, China
| | - Tao Dou
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging,Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital of Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
| | - Qian Yang
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging,Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital of Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
| | - Chunxiao Yu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging,Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital of Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
| | - Qingbo Guan
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging,Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital of Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
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Kolanu ND, Awan NA, Butt AI, Reza T, Almadhoun MKIK, Janoowala T, Bokhari SFH, Zain Z, Sharif T, Chauhan L, Choudhari J. From Antibodies to Artificial Intelligence: A Comprehensive Review of Diagnostic Challenges in Hashimoto's Thyroiditis. Cureus 2024; 16:e54393. [PMID: 38505448 PMCID: PMC10949900 DOI: 10.7759/cureus.54393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2024] [Indexed: 03/21/2024] Open
Abstract
Hashimoto's thyroiditis (HT) poses diagnostic challenges due to its diverse clinical presentation and the intricacies of autoimmune thyroid diseases. This comprehensive narrative review explores the evolving landscape of diagnostic challenges in HT, aiming to provide a thorough understanding of the complexities involved in its diagnosis. The diagnostic criteria for HT involve a multifaceted approach, including clinical features, laboratory findings, and imaging studies. Serum antibodies against thyroid antigens, primarily thyroperoxidase (TPO) and thyroglobulin, play a crucial role in confirming the autoimmune nature of the disease. However, seronegative HT adds complexity by presenting without detectable antibodies. The significance of addressing diagnostic challenges lies in potential delays and misdiagnoses, emphasizing the need for accurate and timely intervention. The review explores future directions, emphasizing molecular and cellular aspects, genetic factors, and the emerging field of thyroid regeneration. Standardized diagnostic criteria are essential, considering the subjective nature of the current process. The heterogeneity of disease manifestations complicates targeted treatments, necessitating a deeper understanding of clinical presentations and underlying pathophysiology. Future research directions and challenges outlined in this review contribute to advancing our understanding and improving diagnostic precision in HT.
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Affiliation(s)
| | | | | | - Taufiqa Reza
- Medicine, Avalon University School of Medicine, Youngstown, USA
| | | | | | | | - Zukhruf Zain
- Family Medicine, Aga Khan University Hospital, Karachi, PAK
| | - Tanzila Sharif
- General Practice, Fatima Jinnah Medical University, Lahore, PAK
| | | | - Jinal Choudhari
- Research & Academic Affairs, Larkin Community Hospital, Miami, USA
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Mydlárová Blaščáková M, Homjáková B, Nagy M, Poráčová J, Lörinczová Z, Makovický P, Kimáková T, Sedlák V, Konečná M. Initial screening of the rs104893657 variant of the PAX8 gene in women with hypothyroidism from Northeastern Slovakia. Cent Eur J Public Health 2023; 31:S89-S94. [PMID: 38272482 DOI: 10.21101/cejph.a7842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 12/15/2023] [Indexed: 01/27/2024]
Abstract
OBJECTIVE Thyroid diseases are among the most common endocrinopathies and metabolic disorders. Hypothyroidism is caused by insufficient production of thyroid hormones with a higher prevalence in women. Causes for the development of endocrine diseases may be mutations in genes that encode peptide hormones. The aim of this scientific study was to determine the genotype and allele frequencies of the rs104893657 variant of the PAX8 gene and to determine the genotype versus phenotype association. METHODS The study population consisted of 135 women from northeastern Slovakia who were divided on the basis of screening into two groups: a control group without diagnosed hypothyroidism (CG = 67) and a group of women with hypothyroidism (HY = 68). Biochemical markers - thyroid-stimulating hormone (TSH), prealbumin (PREA), calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) were determined using Cobas Integra 400 plus, Cobas e411 analysers (Roche). Genotyping was performed using TaqMan® SNP Genotyping Assay instrument 7500 Fast Real-Time PCR Systems (Applied Biosystem). RESULTS Student's t-test revealed a statistically significant difference between CG and HY in biochemical parameters: TSH (p < 0.001), P (p = 0.008). By Chi-square test we found no statistically significant difference in the representation of genotypes (p = 0.788) in the rs104893657 polymorphism of PAX8 gene. The T allele was not associated with hypothyroidism in Slovak women (p = 0.548). In CC genotype we found statistically significant difference between CG and HY in parameters TSH (p < 0.001) and P (p = 0.006). CONCLUSION The mutant T allele was detected at low frequency in both groups of women studied. The association of the T allele with the development of hypothyroidism in Slovak women was not confirmed. The results of this work provide initial information on the distribution of genotypes and alleles in the studied variant of PAX8 gene in the Slovak female population.
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Affiliation(s)
- Marta Mydlárová Blaščáková
- Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Presov, Slovak Republic
| | - Barbora Homjáková
- Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Presov, Slovak Republic
| | - Melinda Nagy
- Department of Biology, Faculty of Education, J. Selye University, Komarno, Slovak Republic
| | - Janka Poráčová
- Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Presov, Slovak Republic
| | | | - Pavol Makovický
- Department of Biology, Faculty of Education, J. Selye University, Komarno, Slovak Republic
| | - Tatiana Kimáková
- Department of Public Health and Hygiene, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovak Republic
| | - Vincent Sedlák
- Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Presov, Slovak Republic
| | - Mária Konečná
- Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Presov, Slovak Republic
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Uccella S, Dottermusch M, Erickson L, Warmbier J, Montone K, Saeger W. Inflammatory and Infectious Disorders in Endocrine Pathology. Endocr Pathol 2023; 34:406-436. [PMID: 37209390 PMCID: PMC10199304 DOI: 10.1007/s12022-023-09771-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2023] [Indexed: 05/22/2023]
Abstract
A variety of inflammatory conditions may directly involve the endocrine glands, leading to endocrine dysfunction that can cause severe consequences on patients' health, if left untreated. Inflammation of the endocrine system may be caused by either infectious agents or other mechanisms, including autoimmune and other immune-mediated processes. Not infrequently, inflammatory and infectious diseases may appear as tumor-like lesions of endocrine organs and simulate neoplastic processes. These diseases may be clinically under-recognized and not infrequently the diagnosis is suggested on pathological samples. Thus, the pathologist should be aware of the basic principles of their pathogenesis, as well as of their morphological features, clinicopathological correlates, and differential diagnosis. Interestingly, several systemic inflammatory conditions show a peculiar tropism to the endocrine system as a whole. In turn, organ-specific inflammatory disorders are observed in endocrine glands. This review will focus on the morphological aspects and clinicopathological features of infectious diseases, autoimmune disorders, drug-induced inflammatory reactions, IgG4-related disease, and other inflammatory disorders involving the endocrine system. A mixed entity-based and organ-based approach will be used, with the aim to provide the practicing pathologist with a comprehensive and practical guide to the diagnosis of infectious and inflammatory disorders of the endocrine system.
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Affiliation(s)
- Silvia Uccella
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanule, Milan, Italy
- Pathology Service IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Matthias Dottermusch
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lori Erickson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN USA
| | - Julia Warmbier
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kathleen Montone
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Wolfgang Saeger
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Ataş PK. A novel hybrid model to predict concomitant diseases for Hashimoto's thyroiditis. BMC Bioinformatics 2023; 24:319. [PMID: 37620755 PMCID: PMC10464155 DOI: 10.1186/s12859-023-05443-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Hashimoto's thyroiditis is an autoimmune disorder characterized by the destruction of thyroid cells through immune-mediated mechanisms involving cells and antibodies. The condition can trigger disturbances in metabolism, leading to the development of other autoimmune diseases, known as concomitant diseases. Multiple concomitant diseases may coexist in a single individual, making it challenging to diagnose and manage them effectively. This study aims to propose a novel hybrid algorithm that classifies concomitant diseases associated with Hashimoto's thyroiditis based on sequences. The approach involves building distinct prediction models for each class and using the output of one model as input for the subsequent one, resulting in a dynamic decision-making process. Genes associated with concomitant diseases were collected alongside those related to Hashimoto's thyroiditis, and their sequences were obtained from the NCBI site in fasta format. The hybrid algorithm was evaluated against common machine learning algorithms and their various combinations. The experimental results demonstrate that the proposed hybrid model outperforms existing classification methods in terms of performance metrics. The significance of this study lies in its two distinctive aspects. Firstly, it presents a new benchmarking dataset that has not been previously developed in this field, using diverse methods. Secondly, it proposes a more effective and efficient solution that accounts for the dynamic nature of the dataset. The hybrid approach holds promise in investigating the genetic heterogeneity of complex diseases such as Hashimoto's thyroiditis and identifying new autoimmune disease genes. Additionally, the results of this study may aid in the development of genetic screening tools and laboratory experiments targeting Hashimoto's thyroiditis genetic risk factors. New software, models, and techniques for computing, including systems biology, machine learning, and artificial intelligence, are used in our study.
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Affiliation(s)
- Pınar Karadayı Ataş
- Department of Computer Engineering, Istanbul Arel University, 34537, Buyukcekmece, Istanbul, Turkey.
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Chiorean AD, Vica ML, Bâlici Ș, Nicula GZ, Răcătăianu N, Bordea MA, Simon LM, Matei HV. The C55A Single Nucleotide Polymorphism in CTLA-4 Gene, a New Possible Biomarker in Thyroid Autoimmune Pathology Such as Hashimoto's Thyroiditis. Diagnostics (Basel) 2023; 13:2517. [PMID: 37568880 PMCID: PMC10417055 DOI: 10.3390/diagnostics13152517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder characterized by the production of autoantibodies against the thyroid gland. Different studies have shown that several genes may be associated with HT, which explains why patients often have family members with thyroiditis or other autoimmune diseases. The aim of this case-control study was to evaluate the correlation between polymorphisms at the level of exon 1 from the CTLA-4 gene and the susceptibility to developing HT. In this study, we found that there is no statistically significant association between the polymorphism rs231775 (A22G in exon 1) of the CTLA-4 gene and a genetic predisposition to HT. In contrast, a strong association was discovered for the first time between C55A in exon 1 of the CTLA-4 gene and HT. Our findings suggest that there is a genetic relationship between the CTLA-4 (+55A/C) genotype and the seropositivity against thyroid autoantigens, such as anti-thyroid peroxidase (ATPO) and anti-thyroglobulin antibodies (ATG).
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Affiliation(s)
- Alin-Dan Chiorean
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Clinical Laboratory, Emergency Clinical Hospital for Children, 400370 Cluj-Napoca, Romania
| | - Mihaela Laura Vica
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Institute of Legal Medicine Cluj-Napoca, 400006 Cluj-Napoca, Romania
| | - Ștefana Bâlici
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
| | - Gheorghe Zsolt Nicula
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
| | - Nicoleta Răcătăianu
- Integrated Ambulatory of Endocrinology, Infectious Diseases Clinical Hospital, 400000 Cluj-Napoca, Romania;
| | - Mădălina Adriana Bordea
- Department of Microbiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.A.B.); (L.-M.S.)
| | - Laura-Mihaela Simon
- Department of Microbiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.A.B.); (L.-M.S.)
| | - Horea Vladi Matei
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Institute of Legal Medicine Cluj-Napoca, 400006 Cluj-Napoca, Romania
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12
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Ghanooni AH, Zadeh-Vakili A, Rezvankhah B, Jafari Nodushan S, Akbarzadeh M, Amouzegar A, Daneshpour MS, Khalili D, Mehrabi Y, Ebadi SA, Azizi F. Longitudinal Associations Between TPO Gene Variants and Thyroid Peroxidase Antibody Seroconversion in a Population-Based Study: Tehran Thyroid Study. Genet Test Mol Biomarkers 2023; 27:65-73. [PMID: 36989526 DOI: 10.1089/gtmb.2022.0122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
Abstract
Introduction: Autoimmune thyroid diseases (AITD) are usually accompanied by anti-thyroid antibodies which can serve as early predictive markers. This study was designed to investigate the relationship between thyroid peroxidase (TPO) gene variants and the presence of TPOAb and to evaluate the effect of environmental factors associated with seroconversion from TPOAb-negative to TPOAb-positive. Methods: Participants from phases 1 and 2 of the Tehran Thyroid Study in (n = 5327, ≥20 years) were evaluated in terms of TPOAb positivity, and its relationship with 53 single nucleotide polymorphisms (SNPs) from within the TPO gene (cross-sectional approach). TPOAb-negative participants (n = 4815) were followed up for seroconversion for 5.5 years. The relationship between the TPO gene variants and the TPOAb seroconversion was evaluated (longitudinal approach). Results: There were 521 TPOAb-positive participants in the cross-sectional phase and 266 new TPOAb-positive cases observed during the follow-up period. After quality control (Hardy-Weinberg equilibrium (p < 1 × 10-5) and minor allele frequency < 0.05), 49 SNPs were qualified for association analyses. From this set fourteen SNPs were identified that were associated with TPOAb positivity. rs6605278, located in the 3'UTR TPO gene, was the most highly significantly associated of the variant and remained associated after adjustment for age, gender, body mass index (BMI), smoking, number of parity, and oral contraceptive consumption in both cross-sectional and longitudinal analyses (p < 0.05). Conclusions: TPOAb-positivity can be partially explained by variants in the TPO gene. New TPOAb-associated SNPs were observed in Iranians as an ethnically diverse population.
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Affiliation(s)
- Amir Hossein Ghanooni
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Zadeh-Vakili
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Boshra Rezvankhah
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Jafari Nodushan
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Akbarzadeh
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Amouzegar
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam S Daneshpour
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Khalili
- Department of Biostatistics and Epidemiology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yadollah Mehrabi
- Department of Biostatistics and Epidemiology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Alireza Ebadi
- Department of Internal Medicine, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Lafontaine N, Wilson SG, Walsh JP. DNA Methylation in Autoimmune Thyroid Disease. J Clin Endocrinol Metab 2023; 108:604-613. [PMID: 36420742 DOI: 10.1210/clinem/dgac664] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/02/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022]
Abstract
Graves disease and Hashimoto disease form part of the spectrum of autoimmune thyroid disease (AITD), to which genetic and environmental factors are recognized contributors. Epigenetics provides a potential link between environmental influences, gene expression, and thyroid autoimmunity. DNA methylation (DNAm) is the best studied epigenetic process, and global hypomethylation of leukocyte DNA is reported in several autoimmune disorders. This review summarizes the current understanding of DNAm in AITD. Targeted DNAm studies of blood samples from AITD patients have reported differential DNAm in the promoter regions of several genes implicated in AITD, including TNF, IFNG, IL2RA, IL6, ICAM1, and PTPN22. In many cases, however, the findings await replication and are unsupported by functional studies to support causal roles in AITD pathogenesis. Furthermore, thyroid hormones affect DNAm, and in many studies confounding by reverse causation has not been considered. Recent studies have shown that DNAm patterns in candidate genes including ITGA6, PRKAA2, and DAPK1 differ between AITD patients from regions with different iodine status, providing a potential mechanism for associations between iodine and AITD. Research focus in the field is moving from candidate gene studies to an epigenome-wide approach. Genome-wide methylation studies of AITD patients have demonstrated multiple differentially methylated positions, including some in immunoregulatory genes such as NOTCH1, HLA-DRB1, TNF, and ICAM1. Large, epigenome-wide studies are required to elucidate the pathophysiological role of DNAm in AITD, with the potential to provide novel diagnostic and prognostic biomarkers as well as therapeutic targets.
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Affiliation(s)
- Nicole Lafontaine
- Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia
- Medical School, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Scott G Wilson
- Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - John P Walsh
- Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia
- Medical School, University of Western Australia, Crawley, Western Australia 6009, Australia
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14
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Xu J, Suo L, Zhao J, Cai T, Mei N, Du P, Gao C, Fang Y, Jiang Y, Zhang JA. MBL2 polymorphism may be a protective factor of autoimmune thyroid disease susceptibility. Mol Genet Genomics 2023; 298:95-105. [PMID: 36318338 DOI: 10.1007/s00438-022-01960-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 09/28/2022] [Indexed: 01/07/2023]
Abstract
Genetic susceptibility is an essential pathogenetic mechanism in autoimmune thyroid disease (AITD). MBL2 gene polymorphisms have been shown to play a vital role in the pathogenesis of multiple autoimmune disorders, but its contribution to AITD is unclear. The aim of this study was to assess the linkage between MBL2 gene polymorphisms and AITD susceptibility in a Chinese Han population. One thousand seven hundred sixty seven subjects consisting of 965 AITD patients and 802 controls from a Chinese Han population were enrolled in the case-control study. Four common single-nucleotide polymorphisms (SNPs) in the MBL2 gene were tested using high-throughput sequencing technology for sequence-based SNP genotyping. The allele and genotype distribution results showed that the minor alleles of rs198266, rs10824793, and rs4935046 were significantly lower in Hashimoto's thyroiditis (HT) patients than in healthy controls. In further genetic model analysis, the dominant models of rs1982266, rs10824793, and rs4935046 for MBL2 in the AITD group exhibited a lower risk of morbidity. Finally, we discovered that haplotype AAGC was associated with Graves' disease (GD), while AGC was associated with HT. Our study provides strong evidence for a genetic correlation between MBL2 and AITD, and the polymorphism of the MBL2 gene may be a protective factor for AITD, especially for HT. These findings can advance our understanding of the etiology of AITD, as well as provide guidance for prevention and intervention toward AITD.
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Affiliation(s)
- Jianbin Xu
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Lixia Suo
- Department of Endocrinology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201899, China
| | - Jing Zhao
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Tiantian Cai
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Na Mei
- Department of Rehabilitation, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Peng Du
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Chaoqun Gao
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Yudie Fang
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China
| | - Yanfei Jiang
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China.
| | - Jin-An Zhang
- Department of Endocrinology and Rheumatology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, 201318, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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15
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Habibullah MM, Hakamy A, Mansor AS, Atti IM, Alwadani AAJ, Kaabi YA. The Association of UCP2-866 G/A Genotype with Autoimmune Hypothyroidism in the Southwestern Saudi Arabia Population. Int J Gen Med 2023; 16:875-879. [PMID: 36910568 PMCID: PMC9999712 DOI: 10.2147/ijgm.s400424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Introduction Autoimmune hypothyroidism (AHT) is a widespread disease that disproportionately affects women over men. It is characterized by the presence of autoantibodies that lead to the dysfunction of the thyroid gland. The exact cause of this process is unknown; however, some factors, such as genetic factors, may be to blame. The uncoupling protein 2 (UCP2) gene encodes uncoupling protein 2, which has been linked to several pathogeneses; however, the link between UCP2-866 G/A polymorphism and AHT has yet to be investigated. Thus, we investigate the potential relationship between UCP2-866 G/A polymorphism and AHT. Methods A total of 158 subjects participated in this study, they were either control or AHT patient, and genotyping was performed using a polymerase chain reaction. Results The frequencies of UCP2-866 G/G, G/A, and A/A in the control subject were 34%, 51%, and 15%, respectively, whereas these frequencies in the AHT were 43%, 46%, and 10%. Conclusion The study concludes a significant relationship between UCP2-866 G/A polymorphism and AHT, with a carrier subject of the -866 A allele being 3 times more likely to suffer from AHT than wild-type carriers in the study population.
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Affiliation(s)
- Mahmoud M Habibullah
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.,Medical Research Center, Jazan University, Jazan, Saudi Arabia
| | - Ali Hakamy
- Department of Respiratory Therapy, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Abdullah S Mansor
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ibrahim Mohammed Atti
- Department of Laboratory and Blood Bank, Prince Mohammed bin Nasser Hospital, Ministry of Health, Jazan, Saudi Arabia
| | - Abbas Ali Jaber Alwadani
- Department of Laboratory and Blood Bank, Prince Mohammed bin Nasser Hospital, Ministry of Health, Jazan, Saudi Arabia
| | - Yahia A Kaabi
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.,Medical Research Center, Jazan University, Jazan, Saudi Arabia
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16
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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17
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Non-Apoptotic Programmed Cell Death in Thyroid Diseases. Pharmaceuticals (Basel) 2022; 15:ph15121565. [PMID: 36559016 PMCID: PMC9788139 DOI: 10.3390/ph15121565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Thyroid disorders are among the most common endocrinological conditions. As the prevalence of thyroid diseases increases annually, the exploration of thyroid disease mechanisms and the development of treatments are also gradually improving. With the gradual advancement of therapies, non-apoptotic programmed cell death (NAPCD) has immense potential in inflammatory and neoplastic diseases. Autophagy, pyroptosis, ferroptosis, and immunogenic cell death are all classical NAPCD. In this paper, we have compiled the recent mechanistic investigations of thyroid diseases and established the considerable progress by NAPCD in thyroid diseases. Furthermore, we have elucidated the role of various types of NAPCD in different thyroid disorders. This will help us to better understand the pathophysiology of thyroid-related disorders and identify new targets and mechanisms of drug resistance, which may facilitate the development of novel diagnostic and therapeutic strategies for patients with thyroid diseases. Here, we have reviewed the advances in the role of NAPCD in the occurrence, progression, and prognosis of thyroid diseases, and highlighted future research prospects in this area.
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18
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Marie MA, McCallen JD, Hamedi ZS, Naqash AR, Hoffman A, Atwell D, Amara S, Muzaffar M, Walker PR, Yang LV. Case Report: Peripheral blood T cells and inflammatory molecules in lung cancer patients with immune checkpoint inhibitor-induced thyroid dysfunction: Case studies and literature review. Front Oncol 2022; 12:1023545. [PMID: 36568170 PMCID: PMC9768626 DOI: 10.3389/fonc.2022.1023545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
Immunotherapy has changed the paradigm of cancer treatment, yet immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 monoclonal antibodies may cause immune-related adverse events (irAEs) in some patients. In this report, two non-small cell lung cancer (NSCLC) patients treated with nivolumab presented with checkpoint inhibitor-induced thyroid dysfunction (CITD), followed by a second irAE of pneumonitis and intestinal perforation, respectively. Increases in peripheral CD8+ T cells correlated with the onset of CITD in the patients. Intriguingly, common inflammatory biomarkers, including C-reactive protein (CRP) and neutrophil/lymphocyte ratio (NLR), were not consistently increased during the onset of CITD but were substantially increased during the onset of pneumonitis and intestinal perforation irAEs. The observations suggest that unlike other irAEs such as pneumonitis, CRP levels and NLR were non-contributory in diagnosing CITD, whereas T cell expansion may be associated with immunotherapy-induced thyroiditis.
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Affiliation(s)
- Mona A. Marie
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Justin D. McCallen
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Zahra S. Hamedi
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Abdul Rafeh Naqash
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States,Department of Internal Medicine, College of Medicine, University of Oklahoma, Oklahoma City, OK, United States
| | - Alexander Hoffman
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Druid Atwell
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Suneetha Amara
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Mahvish Muzaffar
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Paul R. Walker
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States,Circulogene, Birmingham, AL, United States,*Correspondence: Li V. Yang, ; Paul R. Walker,
| | - Li V. Yang
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States,*Correspondence: Li V. Yang, ; Paul R. Walker,
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19
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Ogunsina K, Koru-Sengul T, Rodriguez V, Caban-Martinez AJ, Solle NS, Ahn S, Kobetz-Kerman EN, Lee DJ. Correlates of positive thyroid peroxidase antibodies among firefighters: A cross-sectional-study. J Endocr Soc 2022; 6:bvac125. [PMID: 36111276 PMCID: PMC9469922 DOI: 10.1210/jendso/bvac125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Indexed: 11/19/2022] Open
Abstract
Context Exposure to endocrine disrupting chemicals (EDCs) are associated with underactive thyroid glands, and possibly autoimmunity. Firefighters are exposed to EDCs from flame retardants; however, the prevalence and risk factor associations of thyroid antibodies among firefighters are unknown. Context We aimed to determine the prevalence of thyroid peroxidase antibodies (TPOAb) and associated sociodemographic and occupational risk factors among firefighters. Methods Firefighters attending professional health and safety conferences between November 2018 and January 2020, and with no prior diagnosis of thyroid disease were invited (n = 278) to submit a health survey, blood samples, and complete a thyroid ultrasound. The survey assessed for sociodemographic and occupational characteristics, including a history of familial thyroid disease, smoking, firefighter tenure, and job rank, radiation exposure, and mitigation practices of occupational exposures. Serum thyroid peroxidase antibody (TPOAb) was also assessed. Results Approximately 39.9% of firefighters evaluated had a positive TPOAb test. The mean age for those TPOAb positive was lower than those who tested negative (41.4 ± 7.9 vs 43.1 ± 7.9 years, P = 0.07) but this difference was not significant. Firefighters with a family history of thyroid disease had a statistically significant higher prevalence of TPOAb compared with those without a family history (60.0% vs 37.5%, P = 0.02); this association remained significant after adjusting for sociodemographic and occupational factors (odds ratio 2.99; CI, 1.31-6.85). Conclusion The prevalence of TPOAb is high among firefighters in our study, and family history is a significant determinant of testing positive for TPOAb. Firefighters may benefit from TPOAb and thyroid stimulating hormone tests, and screening for family history of thyroid disease at baseline employee medical check-ups. This finding suggests the need for further studies.
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Affiliation(s)
- Kemi Ogunsina
- Department of Public Health Sciences, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - Tulay Koru-Sengul
- Department of Public Health Sciences, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - Valentina Rodriguez
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - Alberto J Caban-Martinez
- Department of Public Health Sciences, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - Natasha Schaefer Solle
- Department of Medicine Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - Soyeon Ahn
- Department of Educational and Psychological Studies, School of Education and Human Development University of Miami, Miami , FL, USA
| | - Erin N Kobetz-Kerman
- Department of Public Health Sciences, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Department of Medicine Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
| | - David J Lee
- Department of Public Health Sciences, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
- Sylvester Comprehensive Cancer Center, Leonard M. Miller School of Medicine University of Miami, Miami , FL, USA
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20
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Wenzek C, Boelen A, Westendorf AM, Engel DR, Moeller LC, Führer D. The interplay of thyroid hormones and the immune system - where we stand and why we need to know about it. Eur J Endocrinol 2022; 186:R65-R77. [PMID: 35175936 PMCID: PMC9010816 DOI: 10.1530/eje-21-1171] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/17/2022] [Indexed: 11/08/2022]
Abstract
Over the past few years, growing evidence suggests direct crosstalk between thyroid hormones (THs) and the immune system. Components of the immune system were proposed to interfere with the central regulation of systemic TH levels. Conversely, THs regulate innate and adaptive immune responses as immune cells are direct target cells of THs. Accordingly, they express different components of local TH action, such as TH transporters or receptors, but our picture of the interplay between THs and the immune system is still incomplete. This review provides a critical overview of current knowledge regarding the interaction of THs and the immune system with the main focus on local TH action within major innate and adaptive immune cell subsets. Thereby, this review aims to highlight open issues which might help to infer the clinical relevance of THs in host defence in the context of different types of diseases such as infection, ischemic organ injury or cancer.
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Affiliation(s)
- Christina Wenzek
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Anita Boelen
- Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Astrid M Westendorf
- Institute for Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Daniel R Engel
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Lars C Moeller
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Correspondence should be addressed to D Führer;
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21
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Autoimmune thyroid patients with CTLA-4 (+49A/G) GG/AG genotypes have high seropositivity to thyroid peroxidase than thyroglobulin. Meta Gene 2022. [DOI: 10.1016/j.mgene.2022.101010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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22
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Nelson HA, Joshi HR, Straseski JA. Mistaken Identity: The Role of Autoantibodies in Endocrine Disease. J Appl Lab Med 2022; 7:206-220. [PMID: 34996091 DOI: 10.1093/jalm/jfab128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/22/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Autoimmune endocrine diseases can be thought of as a case of mistaken identity. The immune system mistakenly attacks one's own cells, as if they were foreign, which typically results in endocrine gland hypofunction and inadequate hormone production. Type 1 diabetes mellitus and autoimmune thyroid disorders (Hashimoto and Graves diseases) are the most common autoimmune endocrine disorders, while conditions such as Addison disease are encountered less frequently. Autoantibody production can precede clinical presentation, and their measurement may aid verification of an autoimmune process and guide appropriate treatment modalities. CONTENT In this review, we discuss type 1 diabetes mellitus, autoimmune thyroid disorders, and Addison disease, emphasizing their associated autoantibodies and methods for clinical detection. We will also discuss efforts to standardize measurement of autoantibodies. CONCLUSIONS Autoimmune endocrine disease progression may take months to years and detection of associated autoantibodies may precede clinical onset of disease. Although detection of autoantibodies is not necessary for diagnosis, they may be useful to verify an autoimmune process.
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Affiliation(s)
- Heather A Nelson
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Hemant R Joshi
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Joely A Straseski
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
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23
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Luo J, Martucci VL, Quandt Z, Groha S, Murray MH, Lovly CM, Rizvi H, Egger JV, Plodkowski AJ, Abu-Akeel M, Schulze I, Merghoub T, Cardenas E, Huntsman S, Li M, Hu D, Gubens MA, Gusev A, Aldrich MC, Hellmann MD, Ziv E. Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non-Small Cell Lung Cancer. Clin Cancer Res 2021; 27:5131-5140. [PMID: 34244291 PMCID: PMC8815444 DOI: 10.1158/1078-0432.ccr-21-0921] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/28/2021] [Accepted: 07/06/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). EXPERIMENTAL DESIGN In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. RESULTS Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. CONCLUSIONS Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
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Affiliation(s)
- Jia Luo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Victoria L Martucci
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Zoe Quandt
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California
- Diabetes Center, University of California, San Francisco, California
| | - Stefan Groha
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Boston, Massachusetts
| | - Megan H Murray
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine M Lovly
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hira Rizvi
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jacklynn V Egger
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Andrew J Plodkowski
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mohsen Abu-Akeel
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Isabell Schulze
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Taha Merghoub
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eduardo Cardenas
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Min Li
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Donglei Hu
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Matthew A Gubens
- Medical Oncology, University of California San Francisco, San Francisco, California
- Department of Medicine, Weill Cornell Medical Center, New York, New York
| | - Alexander Gusev
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Boston, Massachusetts
| | - Melinda C Aldrich
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew D Hellmann
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical Center, New York, New York
| | - Elad Ziv
- Department of Medicine, University of California San Francisco, San Francisco, California.
- Helen Diller Family Comprehensive Cancer Center, Center for Genes, Environment and Health and Institute for Human Genetics, University of California San Francisco, San Francisco, California
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24
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Qiu K, Li K, Zeng T, Liao Y, Min J, Zhang N, Peng M, Kong W, Chen LL. Integrative Analyses of Genes Associated with Hashimoto's Thyroiditis. J Immunol Res 2021; 2021:8263829. [PMID: 34493981 PMCID: PMC8418929 DOI: 10.1155/2021/8263829] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/18/2021] [Accepted: 08/06/2021] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, is a common autoimmune thyroiditis, which mostly occurs in young and middle-aged women. It can be manifested as hyperthyroidism in the early stage; hypothyroidism may appear with the progression of the disease. Studies have shown that multiple factors such as heredity, environment, and autoimmunity are involved in the pathogenesis, but the specific mechanism is not clear. In our study, we tried to find key genes and potential molecular mechanisms of Hashimoto's thyroiditis to provide new ideas for the therapeutic targets of Hashimoto's thyroiditis. METHOD GSE138198 and GSE54958 were downloaded from the GEO database, and two datasets were combined for analysis. The combined data were normalized to identify the differentially expressed genes (DEGs), and GO and KEGG enrichment analyses were performed. Protein-protein interaction (PPI) networks and hub genes between DEGs were identified. We also used the miRWalk database to identify regulatory miRNAs associated with expressions of DEGs. RESULT We identified 182 DEGs (160 upregulated and 22 downregulated) between Hashimoto's disease patients and the healthy control group. GO analysis showed that DEGs were mostly concentrated in detection of chemical stimulus involved in sensory perception, intermediate filament cytoskeleton, and olfactory receptor activity. KEGG pathway analysis showed that DEGs were mainly related to olfactory transduction. Some members of the KRTAP family and HTR5A, KNG1, DRD3, HTR1D, TAS2R16, INSL5, TAS2R42, and GRM7 are the most important hub genes in the PPI network. In addition, we recognized that OTUD4, LLPH, and ECHDC1 were the most important hub genes in the miRNA-target gene network. CONCLUSION In this study, a series of bioinformatics analyses of DEGs were performed to identify the key genes and pathways associated with Hashimoto's thyroiditis. These genes and pathways provide a more detailed understanding of the pathogenesis of Hashimoto's disease and provide new ideas for the therapeutic targets of Hashimoto's thyroiditis.
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Affiliation(s)
- Kangli Qiu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Kai Li
- Network and Computing Center, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tianshu Zeng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Yunfei Liao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Jie Min
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Nan Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Miaomiao Peng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Lu-lu Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
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25
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Wu H, Zhang W, Zhang Y, Kang Z, Miao X, Na X. Novel insights into di‑(2‑ethylhexyl)phthalate activation: Implications for the hypothalamus‑pituitary‑thyroid axis. Mol Med Rep 2021; 23:290. [PMID: 33649816 PMCID: PMC7930932 DOI: 10.3892/mmr.2021.11930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 09/09/2020] [Indexed: 11/06/2022] Open
Abstract
Di (2‑ethylhexyl) phthalate (DEHP), an environmental pollutant, is widely used as a plasticizer and causes serious pollution in the ecological environment. As previously reported, exposure to DEHP may cause thyroid dysfunction of the hypothalamic‑pituitary‑thyroid (HPT) axis. However, the underlying role of DEHP remains to be elucidated. The present study performed intragastrical administration of DEHP (150, 300 and 600 mg/kg) once a day for 90 consecutive days. DEHP‑stimulated oxidative stress increased the thyroid follicular cavity diameter and caused thyrocyte oedema. Furthermore, DEHP exposure altered mRNA and protein levels. Thus, DEHP may perturb TH homeostasis by affecting biosynthesis, biotransformation, bio‑transportation, receptor levels and metabolism through disruption of the HPT axis and activation of the thyroid‑stimulating hormone (TSH)/TSH receptor signaling pathway. These results identified the formerly unappreciated endocrine‑disrupting activities of phthalates and the molecular mechanisms of DEHP‑induced thyrotoxicity.
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Affiliation(s)
- Haoyu Wu
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Wanying Zhang
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
- Department of Logistics Support, Chengdu Blood Center, Chengdu, Sichuan 610041, P.R. China
| | - Yunbo Zhang
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Zhen Kang
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
- Department of Environmental Hygiene, Harbin Center for Disease Control and Prevention, Harbin, Heilongjiang 150001, P.R. China
| | - Xinxiunan Miao
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xiaolin Na
- Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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26
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Goyal I, Pandey MR, Sharma R, Chaudhuri A, Dandona P. The side effects of immune checkpoint inhibitor therapy on the endocrine system. Indian J Med Res 2021; 154:559-570. [PMID: 35435341 PMCID: PMC9205006 DOI: 10.4103/ijmr.ijmr_313_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte–associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary–adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary–adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.
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Affiliation(s)
- Itivrita Goyal
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Manu Raj Pandey
- Department of Hematology & Oncology, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rajeev Sharma
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Ajay Chaudhuri
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Paresh Dandona
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
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27
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Kotwal A, Gustafson MP, Bornschlegl S, Kottschade L, Delivanis DA, Dietz AB, Gandhi M, Ryder M. Immune Checkpoint Inhibitor-Induced Thyroiditis Is Associated with Increased Intrathyroidal T Lymphocyte Subpopulations. Thyroid 2020; 30:1440-1450. [PMID: 32323619 PMCID: PMC7583332 DOI: 10.1089/thy.2020.0075] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background: Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14+CD16+ monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (n = 9) and peripheral blood (n = 7) as compared with healthy thyroid samples (n = 5) and healthy volunteer blood samples (n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4-CD8- T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8+T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4+PD1+ T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8+PD1+ T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4+CD8+, CD4-CD8- T, gamma-delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8+ and CD4-CD8- T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.
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Affiliation(s)
- Anupam Kotwal
- Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael P. Gustafson
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Svetlana Bornschlegl
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Lisa Kottschade
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Danae A. Delivanis
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Allan B. Dietz
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Manish Gandhi
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mabel Ryder
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
- Address correspondence to: Mabel Ryder, MD, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN 55901, USA
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28
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Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S. Dysregulation of non-coding RNAs in autoimmune thyroid disease. Exp Mol Pathol 2020; 117:104527. [PMID: 32916160 DOI: 10.1016/j.yexmp.2020.104527] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 08/27/2020] [Accepted: 09/05/2020] [Indexed: 12/16/2022]
Abstract
Autoimmune thyroid disease (AITD) is a complex disorder with both genetic and environmental risk factors. A number of genetic factors such as HLA and CTLA-4 loci have been associated with risk of this disorder. In addition to these factors, recent studies have shown contribution of non-coding RNAs in the pathogenesis of this condition. Several microRNAs (miRNAs) and a number of long noncoding RNAs (lncRNAs) such as IFNG-AS1, Heg, NR_038461, NR_038462, T204821 and NR_104125 have been dysregulated in peripheral blood of patients with AITD. These transcripts are mostly enriched in pathways that modulate humoral and cellular immune responses such as those associated with antigen presentation and differentiation of Th1, Th2 and Th17 cells. Functional studies verified the role of a number of lncRNAs and miRNAs in regulation of critical immune-related pathways in AITD. Thus, they participate in the pathophysiology of AITD. In the current review, we summarize the results of studies that assessed participation of non-coding RNAs in the pathophysiology of AITD.
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Affiliation(s)
- Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reyhane Eghtedarian
- Department of Medical genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
| | - Soudeh Ghafouri-Fard
- Department of Medical genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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29
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Root-Bernstein R. Synergistic Activation of Toll-Like and NOD Receptors by Complementary Antigens as Facilitators of Autoimmune Disease: Review, Model and Novel Predictions. Int J Mol Sci 2020; 21:ijms21134645. [PMID: 32629865 PMCID: PMC7369971 DOI: 10.3390/ijms21134645] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 12/29/2022] Open
Abstract
Persistent activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) in the innate immune system is one necessary driver of autoimmune disease (AD), but its mechanism remains obscure. This study compares and contrasts TLR and NOD activation profiles for four AD (autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis) and their animal models. The failure of current AD theories to explain the disparate TLR/NOD profiles in AD is reviewed and a novel model is presented that explains innate immune support of persistent chronic inflammation in terms of unique combinations of complementary AD-specific antigens stimulating synergistic TLRs and/or NODs. The potential explanatory power of the model is explored through testable, novel predictions concerning TLR- and NOD-related AD animal models and therapies.
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30
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Kaabi YA, Mansor AS, Alfagih AS, Hakami AM, Summ MA, Mjery YA, Alzughbi MN, Habibullah MM. Frequency of UCP2 45-bp Ins/Del polymorphism in Saudi population from Jazan area and its association with autoimmune hypothyroidism UCP2 45-bp Ins/Del frequency in hypothyroidism. Int J Health Sci (Qassim) 2020; 14:11-16. [PMID: 32694967 PMCID: PMC7346973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVES Autoimmune hypothyroidism (AHT) is a common endocrine disorder. Although the exact cause of AHT is not yet understood, genetic factors may play a major role. Uncoupling protein 2 (UCP2) is a member of mitochondrial protein family involved in the regulation of cellular metabolism. An important functional polymorphism in the UCP2 gene, 45-bp insertion/deletion (ins/del) polymorphism, has been linked to certain clinical conditions. However, an association between the 45-bp ins/del polymorphism and AHT has not yet been established. METHODS In this study, about 259 blood samples were collected from, patients with AHT and age-matched healthy control subjects. DNA was extracted for UCP2 45-bp ins/del polymorphisms genotyping, using a standard polymerase chain reaction technique. The distribution of different genotypes was determined in both groups and possible association with AHT was also assessed by logistic regression analysis using the Del/Del variant as a reference genotype. RESULTS The frequency of the UCP2 45-bp ins/del polymorphism in the total study population was 49.04%, 40.15%, and 10.81% for Del/Del, Ins/Del, and Ins/Ins genotypes, respectively. The logistic regression analysis showed crude odds ratios (ORs), respectively, with their 95% confidence intervals (CIs) and P-values in codominant (Del/Ins) (OR = 1.53, CI = 0.89-2.60, P = 0.17), codominant (Ins/Ins) (OR = 0.75, CI = 0.34-1.74, P = 0.53), dominant (OR = 1.30, CI = 0.79-2.16, P = 0.37), and recessive (OR = 0.62, CI = 0.29-1.36, P = 0.30) inheritance models tested, where none of which were statistically significant. CONCLUSION Our data revealed the distribution of the UCP2 45-bp ins/del polymorphisms in Jazan area and confirmed the lack of association between these genetic variants and the development of AHT.
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Affiliation(s)
- Yahia A. Kaabi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - Abdullah S. Mansor
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - Ashwag S. Alfagih
- Endocrinology and Diabetes Center, King Fahad Central Hospital, Jazan, Kingdom of Saudi Arabia
| | - Alhussain M. Hakami
- Endocrinology and Diabetes Center, King Fahad Central Hospital, Jazan, Kingdom of Saudi Arabia
| | - Mohammed A. Summ
- Endocrinology and Diabetes Center, King Fahad Central Hospital, Jazan, Kingdom of Saudi Arabia
| | - Yahia A. Mjery
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia,Address for correspondence: Yahia A. Kaabi, Department of Clinical Chemistry, Faculty of Applied Medical Sciences, Jazan University, Kingdom of Saudi Arabia. Mobile: +966 549918001. E-mail:
| | - Mona N. Alzughbi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - Mahmoud M. Habibullah
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
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31
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Calcaterra V, Montalbano C, Miceli E, Luinetti O, Albertini R, Vinci F, Regalbuto C, Larizza D. Anti-gastric parietal cell antibodies for autoimmune gastritis screening in juvenile autoimmune thyroid disease. J Endocrinol Invest 2020; 43:81-86. [PMID: 31264142 DOI: 10.1007/s40618-019-01081-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 06/26/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Patients with autoimmune thyroid disease (ATD) have a higher prevalence of autoimmune gastritis (AIG) compared with the general population. The association between ATD and AIG is poorly characterized in the pediatric age. We reviewed the prevalence of anti-gastric parietal cell antibodies (PCA) in young patients with ATD to evaluate its usefulness as a marker for AIG screening. METHODS We evaluated 220 children and adolescents (11.28 ± 6.37 years) with ATD (186 with autoimmune thyroiditis (AT) and 34 with Graves' disease (GD). At ATD diagnosis and annually thereafter, blood counts and PCA levels were measured. In patients positive for PCA, plasma gastrin, chromogranin A, vitamin B12, iron and ferritin levels and H. pylori antigen were measured. PCA-positive patients > 18 years were invited to undergo a gastroscopic exam. RESULTS PCA positivity was detected in ten (4.5%) subjects (5F/5M; 12.6 ± 3.4 years). The prevalence of PCA positivity was not significantly different in the comparison of GD and AT patients (p = 0.9). PCA positivity was detected after 2.7 ± 2.7 years of follow-up in AT and 4.4 ± 4.0 years in GD (p = 0.4). Autoantibody positivity was more prevalent in female patients, in both AT and GD (p = 0.02 and p = 0.03, respectively). At detection of PCA positivity, five out of ten PCA-positive patients had iron deficiency, four vitamin B12 deficiency, two anemia, three hypergastrinemia and two elevated chromogranin values. Two patients had H. pylori infection. Gastroscopy was performed in the five ATD patients and in all patients, AIG was confirmed. CONCLUSION In the juvenile population, ATD and AIG may also be associated. PCA screening is useful to detect subjects at risk for this condition. Due to the longer life expectancy of the pediatric population and considering the relatively high risk of malignant transformation, early surveillance monitoring is mandatory for children and adolescents with ATD.
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Affiliation(s)
- V Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy.
- Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, P.le Golgi n.2, 27100, Pavia, Italy.
| | - C Montalbano
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, P.le Golgi n.2, 27100, Pavia, Italy
| | - E Miceli
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- University of Pavia, Pavia, Italy
| | - O Luinetti
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Pathology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - R Albertini
- Laboratory of Clinical Chemistry, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - F Vinci
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, P.le Golgi n.2, 27100, Pavia, Italy
| | - C Regalbuto
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, P.le Golgi n.2, 27100, Pavia, Italy
| | - D Larizza
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, P.le Golgi n.2, 27100, Pavia, Italy
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Teniente-Serra A, Soldevila B, Quirant-Sánchez B, Fernández MA, Ester Condins A, Puig-Domingo M, Pujol-Borrell R, Martínez-Cáceres EM. Distinct pattern of peripheral lymphocyte subsets in Graves' disease with persistency of anti-TSHR autoantibodies. Autoimmunity 2019; 52:220-227. [PMID: 31366254 DOI: 10.1080/08916934.2019.1646253] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Background: Graves' disease (GD) is characterized by the production of autoantibodies against the TSHR (TRAbs). With long-term treatment, serum concentrations of TRAbs decline but in some patients, despite being clinically stable, TRAbs persist for many years.Objective: To investigate whether GD patients with persistence of TRAbs constitute a subset of patients that could be identified by phenotypic analysis of circulating lymphocytes, suggesting disease heterogeneity.Materials and methods: Peripheral blood lymphocytes (including naïve, memory and effector T and B cells, Th17, regulatory T cells (Treg), recent thymic emigrants (RTEs) and double positive CD4+CD8+ (DP) cells) were analysed by flow cytometry in a cross-sectional study in 25 clinically stable GD patients, five patients at onset of GD disease and 40 healthy donors (HDs).Results: GD patients with persistence of TRAbs showed a lower percentage of Treg and lower absolute numbers of central and effector memory CD8+ T cells than HD. No differences in RTEs were found in peripheral blood from GD patients compared to HD. Stable GD patients had higher percentage of DP cells of effector phenotype than HD.Conclusions: Using extensive phenotypic analysis of lymphocyte subpopulations, it is possible to detect changes that help to identify patients with persistent TSHR antibodies and may contribute to understand why the autoimmune response is maintained.
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Affiliation(s)
- Aina Teniente-Serra
- Immunology Division, LCMN Germans Trias i Pujol University Hospital Badalona, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain
| | - Berta Soldevila
- Endocrinology and Nutrition Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
| | - Bibiana Quirant-Sánchez
- Immunology Division, LCMN Germans Trias i Pujol University Hospital Badalona, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain
| | - Marco A Fernández
- Flow Cytometry Facility, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
| | | | - Manuel Puig-Domingo
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain.,Endocrinology and Nutrition Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
| | - Ricardo Pujol-Borrell
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Immunology Division, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - Eva M Martínez-Cáceres
- Immunology Division, LCMN Germans Trias i Pujol University Hospital Badalona, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain
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Jannin A, Penel N, Ladsous M, Vantyghem MC, Do Cao C. Tyrosine kinase inhibitors and immune checkpoint inhibitors-induced thyroid disorders. Crit Rev Oncol Hematol 2019; 141:23-35. [PMID: 31202955 DOI: 10.1016/j.critrevonc.2019.05.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/21/2019] [Accepted: 05/27/2019] [Indexed: 12/11/2022] Open
Abstract
Recently, tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICPIs) have emerged as new classes of anticancer therapies. Although generally considered less toxic than cytotoxic chemotherapy, these new drugs can cause significant unanticipated side effects including thyroid dysfunction. This review provides a literature assessment of thyroid dysfunctions induced by TKI and ICPIs. We intend to define for these two classes the frequency of thyroid involvement, the potential mechanisms that result in this toxicity, the clinical-biological impact and the therapeutic management. Detection of thyroid dysfunction requires monitoring of TSH, in combination with free T4 if needed and, depending on the clinical impact and the kinetics of biological abnormalities, starting symptomatic treatment of hyperthyroidism and/or correcting hypothyroidism.
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Affiliation(s)
- Arnaud Jannin
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
| | - Nicolas Penel
- Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France; Medical Oncology Department, CHU Lille, 59037, Lille France.
| | - Miriam Ladsous
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
| | - Marie Christine Vantyghem
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France; UMR 1190 Translational Research in Diabetes INSERM, 59000 Lille, France.
| | - Christine Do Cao
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
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Shin DH, Baek IC, Kim HJ, Choi EJ, Ahn M, Jung MH, Suh BK, Cho WK, Kim TG. HLA alleles, especially amino-acid signatures of HLA-DPB1, might contribute to the molecular pathogenesis of early-onset autoimmune thyroid disease. PLoS One 2019; 14:e0216941. [PMID: 31091281 PMCID: PMC6519818 DOI: 10.1371/journal.pone.0216941] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 05/01/2019] [Indexed: 11/17/2022] Open
Abstract
The major histocompatibility complex region has been suggested to play an important role in the development of autoimmune thyroid disease (AITD). In this study, we investigated the associations of human leukocyte antigen (HLA) alleles and amino acid variants of HLA with early-onset AITD. HLA class I and class II genes were analyzed in 116 Korean children with AITDs (Graves’ disease [GD]: 71, Hashimoto’s disease [HD]: 45) and 142 healthy controls. HLA-B*46:01 (OR = 3.96, Pc = 0.008), -C*01:02 (OR = 2.51 Pc = 0.04), -DPB1*02:02 (OR = 3.99, Pc = 0.04), and -DPB1*05:01 (OR = 4.6, Pc = 0.003) were significantly associated with GD, and HLA-A*02:07 (OR = 4.68, Pc = 0.045) and -DPB1*02:02 (OR = 6.57, Pc = 0.0001) with HD. The frequency of HLA-DPB1*05:01 was significantly higher in GD patients than in HD patients (Pc = 0.0005). Furthermore, differences were found between patients with Thyroid associated ophthalmopathy (TAO) and those without TAO in the distribution of HLA-B*54:01 (8.6% vs. 30.6%, P = 0.04) and -C*03:03 (37.1% vs. 11.1%, P = 0.02). In the analysis of amino acid variants of HLA molecules, both Leu35 (OR = 23.38, P = 0.0002) and Glu55 (OR = 23.38, P = 0.0002) of HLA-DPB1 were strongly associated with GD and showed different distributions between GD and HD (P = 0.001). Our results suggest that HLA alleles, especially amino-acid signatures of the HLA-DP β chain, might contribute to the molecular pathogenesis of early-onset AITD.
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Affiliation(s)
- Dong-Hwan Shin
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In-Cheol Baek
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyung Jae Kim
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eun-Jeong Choi
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Moonbae Ahn
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min Ho Jung
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Byung-Kyu Suh
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Kyoung Cho
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Tai-Gyu Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Abu-Hassan DW, Alhouri AN, Altork NA, Shkoukani ZW, Altamimi TS, Alqaisi OM, Mustafa B. MTHFR gene polymorphisms in hypothyroidism and hyperthyroidism among Jordanian females. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2019; 63:280-287. [PMID: 31066758 PMCID: PMC10522201 DOI: 10.20945/2359-3997000000133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 02/18/2019] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation that is associated with autoimmune pathology. We investigated the association between MTHFR genetic polymorphisms at g.677C>T and g.1298A>C and their haplotypes, and the risk of thyroid dysfunction among Jordanian females. SUBJECTS AND METHODS A case-control study involving 98 hypothyroidism cases, 66 hyperthyroidism cases and 100 controls was conducted. Polymerase chain reaction/restriction fragment length polymorphism technique was performed to determine genotypes. Statistical analysis using SPSS software was performed. RESULTS Genetic analysis showed a significant difference in genotype frequency of g.1298A>C between cases, and controls [hypothyroidism: AA (45.9%), AC (37.8%), CC (16.3%); hyperthyroidism: AA (9.1%), AC (69.7%), CC (21.2%); controls: AA (37.8%), AC (29.6%), CC (32.7%); CChypo vs. AAhypo: 2.55, 95% CI: (1.18-5.52); OR at least on Chypo: 1.79, 95% CI: (1.07-2.99)]; CChyper vs. AAhyper: 4.01, 95% CI: (1.79-9.01); OR at least on Chyper: 0.18, 95% CI: (0.07-0.48)]. There was no significant difference in genotype frequency of g.677C>T between cases and controls [hypothyroidism: CC (50.0%), CT (32.7%), TT (17.3%); hyperthyroidism: CC (77.3%), CT (15.2%), TT (7.6%); controls: CC (55.6%), CT (32.3%), TT (12.1%)]. There was a significant difference of MTHFR haplotypes among hypothyroidism cases and controls. TA and CC had a lower hypothyroidism risk whereas; TC showed a higher risk. CONCLUSIONS g.1298A>C genetic polymorphism of MTHFR may modulate the risk of thyroid disease. CC, TA, and TC haplotypes affect the risk of hypothyroidism. Larger samples should be included in the future to verify the role of MTHFR polymorphisms in thyroid diseases.
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Affiliation(s)
- Diala W Abu-Hassan
- Department of Physiology and Biochemistry, School of Medicine, University of Jordan, Amman, Jordan
| | | | | | | | | | | | - Baha Mustafa
- School of Medicine, University of Jordan, Amman, Jordan
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36
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Wawrusiewicz-Kurylonek N, Koper-Lenkiewicz OM, Gościk J, Myśliwiec J, Pawłowski P, Krętowski AJ. Association of PTPN22 polymorphism and its correlation with Graves' disease susceptibility in Polish adult population-A preliminary study. Mol Genet Genomic Med 2019; 7:e661. [PMID: 30938100 PMCID: PMC6565548 DOI: 10.1002/mgg3.661] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/30/2019] [Accepted: 03/04/2019] [Indexed: 11/16/2022] Open
Abstract
Background Susceptibility to Graves' disease (GD) is determined by various genetic factors; the gene encoding protein tyrosine phosphatase (PTPN22) may be one of those associated with higher risk of GD. The aim was to estimate the association of the PTPN22 gene polymorphism rs2476601:c.C>T (c.1858C>T) with the predisposition to GD within the adult north‐eastern Polish population. Methods PTPN22 gene polymorphism was analyzed in individuals with clinical GD history (n = 166) and healthy subjects (n = 154). The presence of different variants of the investigated gene polymorphism was estimated using the DNA Sanger sequencing method. Results Patients with GD had a more frequent occurrence of the T gene allele of PTPN22 gene compared to the control group, however, it was not significant (p = 0.257). Analysis of genotype distribution showed significantly more frequent occurrence of TT homozygote in GD patients compared to control individuals (p = 0.016, OR = 9.28). Patients with ophthalmopathy had a less frequent occurrence of the T gene allele of PTPN22 gene compared to patients without ophthalmopathy, however, it was not significant (p = 0.12). Occurrence of the T gene allele of PTPN22 gene in GD manifestation in those under 40‐year old was more frequent compared to individuals over 40, but the obtained difference was also not significant (p = 0.75). Conclusions Our preliminary study suggest that PTPN22:c.1858C>T gene polymorphism may be associated with a predisposition to GD within the adult north‐eastern Polish population. The studied polymorphism of the PTPN22 gene did not significantly affect the risk of ophthalmopathy developing and disease manifestation before the age of 40.
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Affiliation(s)
| | | | - Joanna Gościk
- Faculty of Computer Science, Bialystok University of Technology, Bialystok, Poland
| | - Janusz Myśliwiec
- Department of Nuclear Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Przemysław Pawłowski
- Department of Medical Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | - Adam Jacek Krętowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
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Liu J, Mao C, Dong L, Kang P, Ding C, Zheng T, Wang X, Xiao Y. Excessive Iodine Promotes Pyroptosis of Thyroid Follicular Epithelial Cells in Hashimoto's Thyroiditis Through the ROS-NF-κB-NLRP3 Pathway. Front Endocrinol (Lausanne) 2019; 10:778. [PMID: 31824415 PMCID: PMC6880659 DOI: 10.3389/fendo.2019.00778] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/24/2019] [Indexed: 12/17/2022] Open
Abstract
Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disease. In recent years, increasing evidence has proven that the incidence of HT is associated with the excessive iodine intake of the body. In the present study, we measured the status of pyroptosis in thyroid tissues from patients with HT and the effects of excessive iodine on the pyroptosis in thyroid follicular cells (TFCs), in an attempt to illuminate the effects of iodine excess on the development of HT disease. Our results showed that increased pyroptosis occurred in the thyroid tissues of HT patients and that an increase in pyroptosis activity in TFCs was primed by excessive iodine in vitro. This process was mediated by reactive oxygen species (ROS) and activation of the NF-κB signaling pathway. In addition, excessive iodine caused NLRP3 inflammasome activation in TFCs, which promoted TFC pyroptosis. Moreover, the release of interleukin-1β (IL-1β) was closely linked to pyroptosis activation. Taken together, our results suggested that excessive iodine contributed to aberrant activation of pyroptosis in TFCs, which could be a pivotal predisposing factor for HT development.
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Affiliation(s)
- Jiameng Liu
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chaoming Mao
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
- *Correspondence: Chaoming Mao
| | - Liyang Dong
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Liyang Dong
| | - Ping Kang
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chao Ding
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Tingting Zheng
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xuefeng Wang
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yichuan Xiao
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Vukovic R, Zeljkovic A, Bufan B, Spasojevic-Kalimanovska V, Milenkovic T, Vekic J. Hashimoto Thyroiditis and Dyslipidemia in Childhood: A Review. Front Endocrinol (Lausanne) 2019; 10:868. [PMID: 31920978 PMCID: PMC6914680 DOI: 10.3389/fendo.2019.00868] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 11/27/2019] [Indexed: 12/19/2022] Open
Abstract
Hashimoto autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in the pediatric population. Development of AIT is mediated mainly by cellular immune response directed toward thyroid autoantigens, leading to inflammation and impaired function of thyroid gland. Both thyroid dysfunction and inflammation affect the metabolism of plasma lipoproteins. The alterations in lipid profile worsen with the advancement of hypothyroidism, ranging from discrete changes in euthyroid AIT patients, to atherogenic dyslipidemia in the overt hypothyroidism. In this review, characteristics of dyslipidemia in pediatric AIT patients, and the consequences in respect to the risk for cardiovascular disease (CVD) development are discussed. Additionally, benefit of L-thyroxine treatment on serum lipid profile in pediatric AIT patients is addressed. Finally, potential usefulness of novel lipid biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), non-cholesterol sterols, low-density lipoprotein particle size and number, and high-density lipoprotein structure and functionality in AIT patients is also covered. Further longitudinal studies are needed in order to elucidate the long-term cardiovascular outcomes of dyslipidemia in pediatric patients with Hashimoto AIT.
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Affiliation(s)
- Rade Vukovic
- Department of Pediatric Endocrinology, Mother and Child Healthcare Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
- *Correspondence: Rade Vukovic
| | - Aleksandra Zeljkovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | | | - Tatjana Milenkovic
- Department of Pediatric Endocrinology, Mother and Child Healthcare Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia
| | - Jelena Vekic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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Vejrazkova D, Vcelak J, Vaclavikova E, Vankova M, Zajickova K, Duskova M, Vrbikova J, Bendlova B. Genetic predictors of the development and recurrence of Graves' disease. Physiol Res 2018; 67:S431-S439. [PMID: 30484670 DOI: 10.33549/physiolres.934018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Graves' disease affects approximately 3 % of women and 0.5 % of men. The first-choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid-specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants.
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Affiliation(s)
- D Vejrazkova
- Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic.
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40
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Liu W, Zhang QY, Yuan FF, Wang HN, Zhang LL, Ma YR, Ye XP, Zhang MM, Song ZY, Li SX, Du WH, Liang J, Zhang XM, Gao GQ, Zhao SX, Chen FL, Song HD. A dense mapping study of six European AITD susceptibility regions in a large Chinese Han Cohort of Graves' disease. Clin Endocrinol (Oxf) 2018; 89:840-848. [PMID: 30176063 DOI: 10.1111/cen.13847] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/05/2018] [Accepted: 08/30/2018] [Indexed: 01/15/2023]
Abstract
OBJECTIVE We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN Dense mapping studies based on GWAS. PATIENTS A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS After the first replication stage, four SNPs from three regions with Pfirst < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.
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Affiliation(s)
- Wei Liu
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian-Yue Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Fei-Fei Yuan
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Hai-Ning Wang
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Le-Le Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Yu-Ru Ma
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Xiao-Ping Ye
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Man-Man Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Zhi-Yi Song
- Department of Endocrinology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Xian Li
- Department of Endocrinology, Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Hua Du
- Department of Endocrinology, People's Hospital of Linyi, Linyi, China
| | - Jun Liang
- Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, China
| | - Xiao-Mei Zhang
- Department of Endocrinology, The First Hospital Affiliated to Bengbu Medical College, Bengbu, China
| | - Guan-Qi Gao
- Department of Endocrinology, People's Hospital of Linyi, Linyi, China
| | - Shuang-Xia Zhao
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
| | - Feng-Ling Chen
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huai-Dong Song
- The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University (SJTU) School of Medicine, Shanghai, China
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sjögren’s Syndrome and Autoimmune Thyroid Disease: Two Sides of the Same Coin. Clin Rev Allergy Immunol 2018; 56:362-374. [DOI: 10.1007/s12016-018-8709-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Zhang ML, Zhang DM, Wang CE, Chen XL, Liu FZ, Yang JX. Association between thyroglobulin polymorphisms and autoimmune thyroid disease: a systematic review and meta-analysis of case-control studies. Genes Immun 2018; 20:484-492. [PMID: 30139952 DOI: 10.1038/s41435-018-0042-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 06/11/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023]
Abstract
Emerging evidence revealed that thyroglobulin (TG) contributes to the development of autoimmune disease, and the relationship between TG and autoimmune thyroid disease (AITD) is still controversial. The aim of this study was to quantify the association between rs2076740, rs853326, rs180223, and rs2069550 TG polymorphisms and risk of AITD using a meta-analysis approach. We identified all studies that assessed the association between TG polymorphisms and AITD from PubMed, Embase, and Web of Science databases. A total of 3013 cases and 1812 controls from ten case-control studies were included. There was no significant associations found between rs2069550, rs180223, and rs853326 polymorphisms and AITD risk. The association between the rs2076740 polymorphism and AITD risk was significant in the codominant model (P = 0.005), suggesting the CC rs2076740 genotype might be a protective factor for AITD. Sensitivity analysis by removing one or two study changed the results in dominant rs2076740 and rs853326 and rs2069550 allele models (P = 0.016, 0.024, 0.027). Latitude and ethnicity significantly affected the association between rs2076740 and rs2069550 polymorphisms and AITD, indicating their protective effects in allele or dominant model (P = 0.012, 0.012, 0.012, 0.009, 0.009). The association between rs2076740, rs2069550, and rs853326 polymorphisms and AITD risk is significantly affected by study characteristics.
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Affiliation(s)
- Ming-Liang Zhang
- Department of Pharmacy, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang; The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Dong-Ming Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Cai-E Wang
- Department of Pharmacy, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang; The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Xiao-Long Chen
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fang-Zhou Liu
- Henan Province Chinese Medicine Research Institute, Zhengzhou, Henan, China
| | - Jian-Xue Yang
- Department of Neurology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
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Rydzewska M, Góralczyk A, Gościk J, Wawrusiewicz-Kurylonek N, Bossowska A, Krętowski A, Bossowski A. Analysis of chosen polymorphisms rs2476601 a/G - PTPN22, rs1990760 C/T - IFIH1, rs179247 a/G - TSHR in pathogenesis of autoimmune thyroid diseases in children. Autoimmunity 2018; 51:183-190. [PMID: 29973096 DOI: 10.1080/08916934.2018.1486824] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Autoimmune thyroid diseases are multifactorial diseases with a genetic susceptibility and environmental factors. A potential role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, the interferon-induced helicase domain 1 (IFIH1) gene, the thyroid-stimulating hormone receptor (TSHR) gene polymorphisms on autoimmune thyroid diseases (AITDs) in adults has been established unequivocally, but there is still lack of research articles including group of children. Objective and hypotheses: To estimate the association of polymorphisms of PTPN22, IFIH1 and TSH-R genes with the pre-disposition to Graves' disease (GD) and Hashimoto's thyroiditis (HT) in children. METHODS The study was performed in 142 patients with GD, 57 with HT and 160 healthy volunteers. The three single-nucleotide polymorphisms (SNPs): rs2476601 - PTPN22, rs1990760 - IFIH1 and rs179247 - TSHR were genotyped by TaqMan SNP genotyping assay using the real-time PCR. RESULTS Rs2476601 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = .009 with odds ratio [OR] = 2.13). Rs2476601 A alleles were more frequent in patients with HT in comparison to healthy subjects (p = .008, OR = 2.48). Rs1990760 T alleles were more frequent in male patients with GD in comparison to healthy males (p = .003, OR = 3.00). In case of HT patients, rs1990760 T alleles were also more frequent in males compared to healthy subjects (p = .086, OR =2.47). Rs179247 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = 0.039, OR = 1.51). CONCLUSIONS Rs2476601 A/G, Rs1990760 C/T and Rs179247 A/G polymorphisms could contribute to the development of AITDs in children. The main risk factor for rs2476601 and rs179247 is allele A. In case of rs1990760, the main risk factor is allele T.
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Affiliation(s)
- Marta Rydzewska
- a Department of Pediatric Endocrinology , Diabetology with Cardiology Division, Medical University of Białystok , Białystok , Poland
| | - Aleksandra Góralczyk
- a Department of Pediatric Endocrinology , Diabetology with Cardiology Division, Medical University of Białystok , Białystok , Poland
| | - Joanna Gościk
- b Software Department, Faculty of Computer Science , Białystok University of Technology , Białystok , Poland
| | - Natalia Wawrusiewicz-Kurylonek
- c Department of Endocrinology and Diabetes with Internal Medicine , Medical University in Białystok , Białystok , Poland
| | - Anna Bossowska
- d Division of Cardiology , Internal Affairs and Administration Ministry Hospital in Białystok , Białystok , Poland
| | - Adam Krętowski
- c Department of Endocrinology and Diabetes with Internal Medicine , Medical University in Białystok , Białystok , Poland
| | - Artur Bossowski
- a Department of Pediatric Endocrinology , Diabetology with Cardiology Division, Medical University of Białystok , Białystok , Poland
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Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7959707. [PMID: 29992164 PMCID: PMC6016217 DOI: 10.1155/2018/7959707] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/21/2018] [Accepted: 03/26/2018] [Indexed: 01/19/2023]
Abstract
Background To date, studies have shown that polymorphisms in an autophagy-related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves' disease, 292 with Hashimoto's thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves' disease patients than controls, and the ORs were OR = 1.207 (P = 0.022), OR = 1.207 (P = 0.027), and OR = 1.200 (P = 0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P = 0.033) and 1.33 (P = 0.024), while the adjusted ORs for rs13361189 were 1.19 (P = 0.042) and 1.33 (P = 0.026), respectively. No significant difference was found between Hashimoto's thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves' disease patients (OR = 1.195, P = 0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves' disease patients (OR = 0.861, P = 0.044; OR = 0.816, P = 0.017). Conclusions Our study reveals IRGM as a susceptibility gene of AITD and Graves' disease for the first time.
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El Menshawy N, Eissa M, Abdeen HM, Elkhamisy EM, Joseph N. CD58; leucocyte function adhesion-3 (LFA-3) could be used as a differentiating marker between immune and non-immune thyroid disorders. ACTA ACUST UNITED AC 2018; 27:721-727. [PMID: 29706856 PMCID: PMC5910489 DOI: 10.1007/s00580-018-2657-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 02/05/2018] [Indexed: 12/02/2022]
Abstract
The link between Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) has been debated for decades due to the shared pathological and immunological components. Immune intolerance and inappropriate immune reaction against self-thyroid cells are distinctive features of both diseases, but definitive data for the clinical presentation of autoimmune thyroid disease remains unclear. To analyse the expression of T-regulatory cells, CD58, the CD4/CD8 ratio and the neutrophil/lymphocyte ratio and to determine if these parameters could be used as differentiating markers between auto- and non-immune thyroid diseases, 75 patients were enrolled in this study—40 with autoimmune thyroid disease (HT and GD ), 15 with non-immune thyroid disease, and 20 healthy controls. Multicolour flow cytometry was used to analyse CD58, T-regulatory cells (Treg) expressing CD4, CD25, HLA-DR and CD8 using different stained fluorescent labelled monoclonal antibodies. The neutrophils and lymphocyte ratio was also measured. Lower expression of Treg with higher expression of CD58 (LFA-3) was found in the autoimmune diseases when compared with the non-immune and control groups. ROC analysis showed that CD58 with sensitivity 88% and specificity 100% with cut-off value more than or equal to 29.9 indicates Hashimoto’s disease, while lower value indicates colloid goitre, and higher or equal to 29.84 indicates Graves’ disease and lower indicates colloid goitre with 100% sensitivity and specificity. CD58 could be used as differentiating marker between immune and non-immune thyroid disorders.
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Affiliation(s)
- Nadia El Menshawy
- 1Clinical Pathology Department, Hematology Unit, Mansoura Medical School, Mansoura University, Mansoura, Egypt
| | - Mohammed Eissa
- 2Clinical Pathology Department, Faculty of Medicine, Zagazig University and King Khalid University, Zagazig, Egypt
| | - Hanaa M Abdeen
- 3Biochemistry Department, Mansoura Medical School, Mansoura University, Mansoura, Egypt
| | - Enas M Elkhamisy
- 4Internal Medicine Department, Specialized Medicine Hospital, Mansoura Medical School, Mansoura University, Mansoura, Egypt
| | - Nabil Joseph
- 5Community Medicine Department, Mansoura Medical School, Mansoura University, Mansoura, Egypt
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Delivanis DA, Gustafson MP, Bornschlegl S, Merten MM, Kottschade L, Withers S, Dietz AB, Ryder M. Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms. J Clin Endocrinol Metab 2017; 102:2770-2780. [PMID: 28609832 PMCID: PMC5546861 DOI: 10.1210/jc.2017-00448] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/02/2017] [Indexed: 12/21/2022]
Abstract
CONTEXT Thyroid immune-related adverse events (irAEs) in patients treated with programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of the most common adverse effects. Our aim was to determine the incidence and examine the potential mechanisms of anti-PD-1-induced thyroid irAEs. DESIGN Single-center, retrospective cohort study. PATIENTS AND MEASUREMENTS We studied 93 patients with advanced cancer (ages 24 to 82 years; 60% males) who received at least one infusion of pembrolizumab. Thyroid test results and thyroid imaging modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral blood was performed. RESULTS Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in seven patients (54%), from which four recovered. New onset of hypothyroidism overt/subclinical developed in three patients. Levothyroxine dosing required doubling in three patients with a known history of hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1-treated patients. CONCLUSIONS Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis and overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment.
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Affiliation(s)
- Danae A. Delivanis
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota 55905
| | - Michael P. Gustafson
- Human Cell Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905
| | - Svetlana Bornschlegl
- Department of Laboratory Medicine & Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905
| | - Michele M. Merten
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota 55905
| | - Lisa Kottschade
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905
| | - Sarah Withers
- Department of Laboratory Medicine & Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905
| | - Allan B. Dietz
- Human Cell Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905
| | - Mabel Ryder
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota 55905
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905
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Wang D, Chen J, Zhang H, Zhang F, Yang L, Mou Y. Role of Different CD40 Polymorphisms in Graves' Disease and Hashimoto's Thyroiditis. Immunol Invest 2017; 46:544-551. [PMID: 28742400 DOI: 10.1080/08820139.2017.1319382] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Genome-wide association studies have led to the discovery of several susceptibility genes related to autoimmune thyroid diseases (AITDs). However, controversial results have been reported regarding the role of single-nucleotide polymorphism (SNP) of CD40 in the disease susceptibility. The objective of this study was to identify the relationship of the polymorphisms of three sites of CD40 with the susceptibility to AITD in the Chinese population. We genotyped three polymorphisms of CD40: C/T -1 SNP, 58038T site of the third exon and C64610G site of the ninth exon in 196 GD cases, 121 HT cases and 122 control subjects. The three putative polymorphism sites were amplified by PCR for sequencing and analysis. The genotype frequencies of CD40 -1 C/C genotype and C allele were significantly higher in the GD group than those in normal control. For the C64610G polymorphism, the C/G genotype was significantly more frequent in HT group than in control group, and the G allele frequencies in the GD and HT group were both higher than those in control group. These results indicated that there exist different susceptibility loci for AITD within CD40, each contributing a different effect in the onset and development of AITDs.
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Affiliation(s)
- Dongguo Wang
- a Department of Clinical Lab Medicine , Taizhou Municipal Hospital, Taizhou University , Taizhou , Zhejiang , China
| | - Jiayu Chen
- b Department of Laboratory Medicine , School of Medicine, Taizhou University , Taizhou , Zhejiang , China
| | - Huanyuan Zhang
- c Department of Pathology , Taizhou Municipal Hospital, Taizhou University , Taizhou , Zhejiang , China
| | - Fangfang Zhang
- c Department of Pathology , Taizhou Municipal Hospital, Taizhou University , Taizhou , Zhejiang , China
| | - Linjun Yang
- d Department of Thyroid-Breast Surgery , Taizhou Municipal Hospital, Taizhou University , Taizhou , Zhejiang , China
| | - Yonghua Mou
- e Department of Hepatobiliary Surgery , Taizhou Municipal Hospital, Taizhou University , Taizhou , Zhejiang , China
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Zaghlol RY, Haghighi A, Alkhayyat MM, Theyab OF, Owaydah AM, Massad MM, Atari MA, Zayed AA. Consanguinity and the Risk of Hashimoto's Thyroiditis. Thyroid 2017; 27:390-395. [PMID: 28061551 DOI: 10.1089/thy.2016.0495] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease that may lead to hypothyroidism due to progressive destruction of the thyroid. The etiology of HT is unclear. However, it is associated with multiple genetic predispositions. Consanguinity has been associated with an increased susceptibility to different inherited conditions. This study investigated the association between consanguinity and risk of HT for the first time. METHODS Using a case-control study design, 298 HT patients were compared with two subject groups: (i) 299 participants with non-HT hypothyroidism, and (ii) 298 healthy control participants. The three groups were age and sex matched. Presence of consanguinity among the parents was compared in these groups, and odds ratios (OR) were calculated to establish a correlation. RESULTS Consanguinity significantly increased the risk of HT (compared with healthy subjects; OR = 3.3; p < 0.0001). In addition, consanguinity was a significant risk factor for HT compared with non-HT hypothyroidism patients (OR = 2.8; p < 0.0001). However, the prevalence of consanguinity was not significantly different in non-HT hypothyroidism patients and healthy subjects. CONCLUSIONS The results suggest that the risk for HT is increased in consanguineous unions, but no significant increase in the risk of non-HT hypothyroidism was observed. However, for more precise risk estimates, larger studies that include different populations may be helpful. These findings highlight the health impact of consanguinity and have applications in empiric risk estimations in genetic counseling, particularly in countries with high rates of consanguineous marriages.
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Affiliation(s)
- Raja Y Zaghlol
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
| | - Alireza Haghighi
- 2 Department of Genetics, Harvard Medical School , Boston, Massachusetts
- 3 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts
- 4 Howard Hughes Medical Institute , Chevy Chase, Maryland
- 5 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts
- 6 Broad Institute of MIT and Harvard , Cambridge, Massachusetts
| | - Motasem M Alkhayyat
- 7 Department of Internal Medicine, Prince Hamza Hospital , The Ministry of Health, Amman, Jordan
| | - Othman F Theyab
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
| | - Amal M Owaydah
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
| | - Mu'taz M Massad
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
| | - Mohammad A Atari
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
| | - Ayman A Zayed
- 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital , Amman, Jordan
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Nordio M, Basciani S. Treatment with Myo-Inositol and Selenium Ensures Euthyroidism in Patients with Autoimmune Thyroiditis. Int J Endocrinol 2017; 2017:2549491. [PMID: 28293260 PMCID: PMC5331475 DOI: 10.1155/2017/2549491] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/27/2016] [Accepted: 11/21/2016] [Indexed: 01/06/2023] Open
Abstract
Clinical evidences have highlighted the efficacy of myo-inositol and selenium in the treatment of autoimmune thyroiditis. Aim of this study was to further analyze the role of myo-inositol plus selenium (Myo-Ins-Se) in restoring a normal thyroid function of Hashimoto's patients with subclinical hypothyroidism. Eighty-six patients with Hashimoto's thyroiditis having thyroid-stimulating hormone (TSH) levels between 3 and 6 mIU/L, elevated serum antithyroid peroxidase (TPOAb) and/or antithyroglobulin (TgAb), and normal free thyroxine (fT4) and free triiodothyronine (fT3) levels were enrolled in the study: one hyperthyroid subject with TSH about 0.14 μU/ml was included in this trial as a single case. Patients were assigned to receive Myo-Ins-Se. TSH, TPOAb, and TgAb levels were significantly decreased in patients treated with combined Myo-Ins-Se after 6 months of treatment. In addition, a significant fT3 and fT4 increase, along with an amelioration of their quality of life, was observed. Remarkably, TSH values of the hyperthyroid patient increased from 0.14 μU/ml up to 1.02 μU/ml, showing a complete restoration of TSH values at a normal range. In conclusion, the administration of Myo-Ins-Se is significantly effective in decreasing TSH, TPOAb, and TgAb levels, as well as enhancing thyroid hormones and personal wellbeing, therefore restoring euthyroidism in patients diagnosed with autoimmune thyroiditis.
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Affiliation(s)
- Maurizio Nordio
- Department of Experimental Medicine, University “Sapienza”, Rome, Italy
| | - Sabrina Basciani
- Department of Experimental Medicine, University “Sapienza”, Rome, Italy
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Wang X, Cheng W, Ma Y, Zhu J. Vitamin D receptor gene FokI but not TaqI, ApaI, BsmI polymorphism is associated with Hashimoto's thyroiditis: a meta-analysis. Sci Rep 2017; 7:41540. [PMID: 28134349 PMCID: PMC5278388 DOI: 10.1038/srep41540] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 12/22/2016] [Indexed: 02/05/2023] Open
Abstract
Four VD receptor (VDR) gene polymorphisms (TaqI, ApaI, FokI and BsmI) have been reported to influence Hashimoto’s thyroiditis (HT) risk. However, individual studies have produced inconsistent results. We conducted a comprehensive meta-analysis of eleven case-control studies to better understand roles of the four polymorphisms in HT development. The results showed only FokI polymorphism was significantly associated with the risk of HT (F vs f: OR = 1.44, 95% CI = 1.09–1.91, P = 0.010; FF vs Ff + ff: OR = 1.72, 95% CI = 1.09–2.70, P = 0.019). Subgroup analyses demonstrated the significant effect was only present in Asian population (F vs f: OR = 1.45, 95% CI = 1.07–1.95, P = 0.016; FF vs ff: OR = 1.64, 95% CI = 1.03–2.59, P = 0.036; FF + Ff vs ff: OR = 1.34, 95% CI = 1.00–1.80, P = 0.047; FF vs Ff + ff: OR = 1.64, 95% CI = 1.03–2.64, P = 0.039), but not in Caucasian. For TaqI, ApaI and BsmI polymorphisms, no significant association was found in any model comparison. Based on the current literature, it appears that only VDR FokI polymorphism is associated with HT risk in Asian population, but not in Caucasians; and the TaqI, ApaI and BsmI polymorphisms have not positive association neither in the overall population, nor when stratified by ethnicity. Further well-designed studies with larger sample sizes and different ethnic population are needed to clarify the present findings.
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Affiliation(s)
- Xiaofei Wang
- Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chendu, China.,Department of General Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Wenli Cheng
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yu Ma
- Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chendu, China
| | - Jingqiang Zhu
- Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chendu, China
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