RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS. METHODS: A review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment. RESULTS: Children with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05). CONCLUSIONS: rhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.

Assuntos

Genótipo , Hormônio do Crescimento Humano , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , Hormônio do Crescimento Humano/uso terapêutico , Criança , Feminino , Masculino , Pré-Escolar , Fator de Crescimento Insulin-Like I , Adolescente , Resultado do Tratamento , Proteínas Recombinantes/uso terapêutico , Lactente , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/genética , Resistência à Insulina

RESUMO

BACKGROUND: In this study, we explored the impact of hypothyroidism and thyroid hormone replacement therapy on the risk of developing cardiovascular diseases, including myocardial infarction, heart failure, and cardiac death, via Mendelian randomization analysis. METHODS: Genetic instrumental variables related to hypothyroidism, levothyroxine treatment (refer to Participants were taking the medication levothyroxine sodium) and adverse cardiovascular events were obtained from a large publicly available genome-wide association study. Two-sample Mendelian randomization analysis was performed via inverse-variance weighting as the primary method. To ensure the reliability of our findings, we performed MR‒Egger regression, Cochran's Q statistic, and leave-one-out analysis. Additionally, multivariable Mendelian randomization was employed to regulate confounding factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), diabetes, cholesterol, low-density lipoprotein (LDL), triglycerides and metformin. A mediation analysis was conducted to assess the mediating effects on the association between exposure and outcome by treating atrial fibrillation and stroke as mediator variables of levothyroxine treatment and bradycardia as mediator variables of hypothyroidism. RESULTS: Genetically predicted hypothyroidism and levothyroxine treatment were significantly associated with the risk of experiencing myocardial infarction [levothyroxine: odds ratio (OR) 3.75, 95% confidence interval (CI): 1.80-7.80; hypothyroidism: OR: 15.11, 95% CI: 2.93-77.88]. Levothyroxine treatment was also significantly related to the risk of experiencing heart failure (OR: 2.16, 95% CI: 1.21-3.88). However, no associations were detected between hypothyroidism and the risk of experiencing heart failure or between hypothyroidism or levothyroxine treatment and the risk of experiencing cardiac death. After adjusting for confounding factors, the results remained stable. Additionally, mediation analysis indicated that atrial fibrillation and stroke may serve as potential mediators in the relationships between levothyroxine treatment and the risk of experiencing heart failure or myocardial infarction. CONCLUSION: The results of our study suggest a positive association between hypothyroidism and myocardial infarction and highlight the potential effects of levothyroxine treatment, the main thyroid hormone replacement therapy approach, on increasing the risk of experiencing myocardial infarction and heart failure.

Assuntos

Doenças Cardiovasculares , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipotireoidismo , Análise da Randomização Mendeliana , Tiroxina , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia , Tiroxina/uso terapêutico , Medição de Risco , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/diagnóstico , Terapia de Reposição Hormonal/efeitos adversos , Fatores de Risco , Fenótipo , Feminino , Infarto do Miocárdio/genética , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/diagnóstico , Polimorfismo de Nucleotídeo Único , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Masculino , Variantes Farmacogenômicos , Fatores de Risco de Doenças Cardíacas

RESUMO

Objective: Observational studies have shown positive associations between thyroid dysfunction and risk of sarcopenia. However, the causality of this association remains unknown. This study aimed to evaluate the potential causal relationship between thyroid dysfunction and sarcopenia using Mendelian randomization (MR). Methods: This study collected pooled data from genome-wide association studies focusing on thyroid dysfunction and three sarcopenia-related features: low hand grip strength, appendicular lean mass (ALM), and walking pace, all in individuals of European ancestry. The primary analytical method used was inverse-variance weighted, with weighted median and MR-Egger serving as complementary methods to assess causal effects. Heterogeneity and pleiotropy tests were also performed, and the stability of the results was evaluated using the Leave-one-out. Results: The MR analysis indicated that hyperthyroidism could lead to a significant decrease in ALM in the extremities (OR = 1.03; 95% CI = 1.02 to 1.05; P < 0.001). The analysis also found that hypothyroidism could cause a notable reduction in grip strength (OR = 2.03; 95% CI = 1.37 to 3.01; P < 0.001) and walking pace (OR = 0.83; 95% CI = 0.77 to 0.90; P < 0.001). There was a significant association between subclinical hyperthyroidism and a reduced walking pace (OR = 1.00; 95% CI = 0.99 to 1.00; P = 0.041). Conclusion: This study provides evidence that hyperthyroidism, hypothyroidism, and subclinical hyperthyroidism can all increase the risk of sarcopenia.

Assuntos

Estudo de Associação Genômica Ampla , Força da Mão , Hipertireoidismo , Análise da Randomização Mendeliana , Sarcopenia , Humanos , Sarcopenia/genética , Sarcopenia/epidemiologia , Força da Mão/fisiologia , Hipertireoidismo/genética , Hipertireoidismo/complicações , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia , Hipotireoidismo/fisiopatologia , Feminino , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/complicações , Masculino

RESUMO

OBJECTIVE: Some correlations between thyroid disorders and insomnia have been found in previous studies; however, the causal relationship between them is unclear. The aim of this study was to investigate the causal relationship between insomnia and five thyroid disorders (hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodules, and thyroid cancer). METHODS: We assessed the causal relationship between insomnia and thyroid disorders using inverse variance weighted, weighted median, and Mendelian randomization (MR)-Egger analyses in MR analyses and then used inverse MR analyses to assess the causal relationship between thyroid disorders and insomnia. RESULTS: MR analysis showed that insomnia did not increase the risk of hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodules, and thyroid cancer. However, reverse MR analysis showed that thyroid cancer increased the risk of insomnia (OR = 1.01, 95%CI: 1.00-1.02, p = .01), and the other four thyroid disorders had no direct causal relationship with insomnia. Sensitivity analyses indicated that the results were robust and no pleiotropy or heterogeneity was detected. CONCLUSION: This study did not find evidence of a bidirectional causal relationship between genetically predicted insomnia and hyperthyroidism, hypothyroidism, thyroiditis, and thyroid nodules. However, we found that although insomnia does not increase the risk of thyroid cancer, thyroid cancer does increase the risk of insomnia.

Assuntos

Análise da Randomização Mendeliana , Distúrbios do Início e da Manutenção do Sono , Doenças da Glândula Tireoide , Humanos , Distúrbios do Início e da Manutenção do Sono/genética , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/complicações , Hipertireoidismo/genética , Hipertireoidismo/complicações , Hipertireoidismo/epidemiologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/epidemiologia , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/epidemiologia

RESUMO

Background: The interinfluence of thyroid function and daily physical activity (PA) remains unclear. We examined the causal relationship between genetically proxied thyroid-related traits; hypothyroidism, hyperthyroidism, thyroid stimulating hormone (TSH) and free thyroxine (FT4), and daily PA measures; leisure screen time (LST) and moderate-to-vigorous physical activity (MVPA), using Mendelian randomisation (MR) analysis. Methods: We used genome-wide association study (GWAS) data from the ThyroidOmics Consortium and the most comprehensive meta-analysis on PA, comprising data on hypothyroidism (n = 53 423), hyperthyroidism (n = 51 823), TSH within the reference range (n = 54 288), fT4 within the reference range (n = 49 269), LST (n = 526 725), and MVPA (n = 608 595) to conduct a bidirectional two-sample MR analysis. The inverse variance weighted (IVW) method was employed as the primary result. Sensitivity analyses included MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) regression. Similar investigations were conducted in the reverse direction. Finally, we analysed a multivariable MR using body mass index (BMI)-related traits GWAS data. Results: In the primary IVW analysis, an increase in genetically proxied TSH levels significantly increased LST (correlation coefficient (ß) = 0.040; 95% confidence interval (CI) = 0.020-0.061, P = 9.776 × 10-5). The multivariable MR analysis indicated that the positive causal effect still existed when considering the influence of BMI (MVMR-IVW: ß = 0.042; 95% CI = 0.011-0.073, P = 0.007). Conversely, there was no evidence to suggest that PA impacts thyroid function. Conclusions: The results of this MR analysis suggest that thyroid function influences daily PA. The positive association between TSH and LST is not confounded or mediated by BMI.

Assuntos

Exercício Físico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Comportamento Sedentário , Humanos , Exercício Físico/fisiologia , Tireotropina/sangue , Testes de Função Tireóidea , Glândula Tireoide , Hipertireoidismo/genética , Hipotireoidismo/genética , Tiroxina/sangue

RESUMO

BACKGROUND: Previous studies have shown an association between acute respiratory distress syndrome (ARDS) and thyroid function. However, their causal relationship remains unspecified. Therefore, this study aims to explore the causal relationship between ARDS and thyroid function-related diseases with Mendelian Randomization (MR) analysis. METHODS: ARDS dataset finn-b-J10_ARDS, finn-b-E4_THYROID dataset of disorders of the thyroid gland (DTG) and finn-b-E4_HYTHYNAS of hypothyroidism were acquired from public database. In univariate MR (UVMR), causal effects between DTG, hypothyroidism and ARDS were investigated using 5 types of algorithms, and reliability was validated by sensitivity analysis. Moreover, multivariate MR (MVMR), enrichment and interaction network analyses of genes corresponding to SNPs of DTG and hypothyroidism were carried out. Significant level was chosen as p<0.05. RESULTS: UVMR identified DTG and hypothyroidism (P < 0.05, OR > 1) as risk factors, and were causally related to ARDS. Reliability of UVMR results was confirmed through sensitivity analysis, and results were stable and reliable. However, DTG and hypothyroidism had no effect on ARDS in MVMR, possibly because these factors had independent effects on ARDS. Ultimately, 96 and 113 genes corresponding to SNPs of DTG and hypothyroidism were found closely related to immune-related pathways. CONCLUSIONS: UVMR and MVMR analysis revealed a causal connection between DTG and hypothyroidism as risk factors with ARDS, providing robust evidence for investigation into relationship of hypothyroidism on ARDS and between DTG and ARDS.

Assuntos

Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório , Humanos , Síndrome do Desconforto Respiratório/genética , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia , Predisposição Genética para Doença , Glândula Tireoide/patologia , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/epidemiologia , Fatores de Risco

RESUMO

An association between thyroid function and multiple sclerosis (MS) has been reported in several observational studies, but the causal relationship between them is still unclear. Thus, this study used a bidirectional Mendelian randomization (MR) to investigate the associations between thyroid function and MS. Bidirectional MR was used to explore the causal relationship between thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [FT4], hyperthyroidism, and hypothyroidism) and MS. Genome-wide association study (GWAS) data of thyroid function and MS were obtained from the ThyroidOmics Consortium and the FinnGen Consortium, respectively. Inverse-variance weighted method (IVW) was the primary analysis method to assess causality with Weighted median, MR-Egger regression, weighted mode, and simple mode as auxiliary methods. Sensitivity analyses were performed using heterogeneity tests, horizontal pleiotropy tests and leave-one-out method. There was a positive causal relationship between TSH and MS (IVW: OR = 1.202, 95% CI: 1.040-1.389, P = .013), and no strong evidence was found for an effect of FT4 (IVW: OR = 1.286, 95% CI: 0.990-1.671, P = .059), hypothyroidism (IVW: OR = 1.247, 95% CI: 0.961-1.617, P = .096), and hyperthyroidism (IVW: OR = 0.966, 95% CI: 0.907-1.030, P = .291) on the risk of MS. In the reverse MR results, there was no causal relationship between MS and TSH (IVW: ß = -0.009, P = .184), FT4 (IVW: ß = -0.011, P = .286), hypothyroidism (IVW: OR = 0.992, 95% CI: 0.944-1.042, P = .745), and hyperthyroidism (IVW: OR = 1.026, 95% CI: 0.943-1.117, P = .549). Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and Leave-one-out did not observe horizontal pleiotropy and heterogeneity. In conclusion, MR analysis supported a positive causal relationship between TSH and MS.

Assuntos

Estudo de Associação Genômica Ampla , Hipertireoidismo , Análise da Randomização Mendeliana , Esclerose Múltipla , Tireotropina , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/epidemiologia , Tireotropina/sangue , Hipertireoidismo/genética , Hipertireoidismo/epidemiologia , Testes de Função Tireóidea , Hipotireoidismo/epidemiologia , Hipotireoidismo/genética , Glândula Tireoide/fisiopatologia , Tiroxina/sangue , Causalidade

RESUMO

Objective: Observational studies have revealed a higher probability of hypothyroidism in patients with dermatomyositis (DM) or polymyositis (PM), but there is no consensus on whether hypothyroidism causally influences DM or PM. In the present study, we assessed the causal association between hypothyroidism and the risk of dermatomyositis or polymyositis using two-sample Mendelian randomization (TSMR). Methods: The genome-wide association data of hypothyroidism and dermatomyositis/polymyositis were obtained from the IEU Open GWAS project. Then, TSMR was used to determine whether hypothyroidism is causally associated with DM or PM. Single-nucleotide polymorphisms (SNPs) significantly associated with hypothyroidism were identified and used as instrumental variables (IVs), and the causal relationship between hypothyroidism and DM/PM was examined using TSMR. MR pleiotropy and Cochran's Q test were used to confirm the heterogeneity and pleiotropy of identified IVs, then four different models, including the inverse variance weighted model (IVW), MR-Egger, weighted median and weighted model were applied in this MR analysis. Results: Sixty-eight SNPs for DM and 68 SNPs for PM were selected as the IVs (P<5×10-8; linkage disequilibrium R2 <0.001) to assess the causal association between hypothyroidism and DM/PM selected from GWASs on hypothyroidism. The results revealed a positive causal effect of hypothyroidism on both DM and PM (DM: OR 2.563, 95% CI [1.348, 4.874], P = 0.00156; PM: OR1.709, 95% CI [1.157, 2.525], P =0.007). Moreover, there was no heterogeneity or pleiotropy in the results. Conclusion: In conclusion, the MR analysis results provided strong evidence to indicate that hypothyroidism might be causally associated with DM and PM. These findings may have important implications for the pathogenesis and possible future therapies of DM/PM.

Assuntos

Estudo de Associação Genômica Ampla , Hipotireoidismo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Hipotireoidismo/genética , Hipotireoidismo/complicações , Hipotireoidismo/epidemiologia , Polimiosite/genética , Polimiosite/complicações , Polimiosite/epidemiologia , Dermatomiosite/genética , Dermatomiosite/complicações , Dermatomiosite/epidemiologia , Predisposição Genética para Doença

RESUMO

OBJECTIVE: To explore the causal relationship between thyroid dysfunction and sepsis based on the bidirectional two-sample Mendelian randomization (MR) method. METHODS: The genome-wide association study (GWAS) dataset were selected to screen single nucleotide polymorphisms (SNP) associated with thyroid dysfunction as instrumental variable (IV) for genetic variation, using hypothyroidism and hyperthyroidism as exposure factor and sepsis as outcome factor. Potential causal relationship between thyroid dysfunction and sepsis was analyzed using a bidirectional two-sample MR method primary analysis method of inverse-variance weighted (IVW). Potential pleiotropic analysis of SNP was performed using the MR Egger regression intercept test. Sensitivity analysis was performed using the "leave one out" test. Reverse MR method was used to prove the causal relationship. RESULTS: The GWAS data were screened based on the three main assumptions of MR, resulting in 101 SNP strongly associated with hypothyroidism and 10 SNP strongly associated with hyperthyroidism entering the MR analysis. The results of the MR using the IVW method showed that the risk of sepsis in individuals with hypothyroidism was 2.293 times higher than those without hypothyroidism [odds ratio (OR) = 2.293, 95% confidence interval (95%CI) was 1.199-4.382, P = 0.012]. There was no significant difference in the risk of sepsis between hyperthyroid and non-hyperthyroid populations (OR = 1.049, 95%CI was 0.999-1.100, P = 0.560). MR Egger regression intercept test showed that the included SNP did not have pleiotropy, and the MR-PRESSO test did not find outliers. Sensitivity analysis suggested that the results of MR were stable. The results of the reverse MR analysis showed that the reverse causal relationship between hyperthyroidism and sepsis was not proved (OR = 0.996, 95%CI was 0.988-1.004, P = 0.338), which further confirmed the robust MR analysis result. CONCLUSIONS: The results of the bidirectional two-sample MR analysis show that hypothyroidism can increase the risk of sepsis onset, while there is no causal relationship between hyperthyroidism and sepsis.

Assuntos

Estudo de Associação Genômica Ampla , Hipertireoidismo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Sepse , Humanos , Sepse/genética , Sepse/complicações , Hipertireoidismo/genética , Hipertireoidismo/complicações , Hipotireoidismo/genética , Fatores de Risco , Doenças da Glândula Tireoide/genética

RESUMO

BACKGROUND: Many studies have investigated the association between hypothyroidism and frozen shoulder, but their findings have been inconsistent. Furthermore, earlier research has been primarily observational, which may introduce bias and does not establish a cause-and-effect relationship. To ascertain the causal association, we performed a two-sample bidirectional Mendelian randomization (MR) analysis. METHODS: We obtained data on "Hypothyroidism" and "Frozen Shoulder" from Summary-level Genome-Wide Association Studies (GWAS) datasets that have been published. The information came from European population samples. The primary analysis utilized the inverse-variance weighted (IVW) method. Additionally, a sensitivity analysis was conducted to assess the robustness of the results. RESULTS: We ultimately chose 39 SNPs as IVs for the final analysis. The results of the two MR methods we utilized in the investigation indicated that a possible causal relationship between hypothyroidism and frozen shoulder. The most significant analytical outcome demonstrated an odds ratio (OR) of 1.0577 (95% Confidence Interval (CI):1.0057-1.1123), P = 0.029, using the IVW approach. Furthermore, using the MR Egger method as a supplementary analytical outcome showed an OR of 1.1608 (95% CI:1.0318-1.3060), P = 0.017. Furthermore, the results of our sensitivity analysis indicate that there is no heterogeneity or pleiotropy in our MR analysis. In the reverse Mendelian analysis, no causal relationship was found between frozen shoulders and hypothyroidism. CONCLUSION: Our MR analysis suggests that there may be a causal relationship between hypothyroidism and frozen shoulder.

Assuntos

Bursite , Estudo de Associação Genômica Ampla , Hipotireoidismo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia , Bursite/genética , Bursite/epidemiologia , Predisposição Genética para Doença

RESUMO

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by progressive fibrosis, leading to impaired gas exchange and high mortality. The etiology of IPF is complex, with potential links to autoimmune disorders such as hypothyroidism. This study explores the relationship between hypothyroidism and IPF, focusing on the mediating role of plasma proteins. Methods: A two-sample Mendelian randomization (MR) approach was employed to determine the impact of hypothyroidism on IPF and the mediating role of 4,907 plasma proteins, all in individuals of European ancestry. Sensitivity analyses, external validation, and reverse causality tests were conducted to ensure the robustness of the findings. Additionally, the function of causal SNPs was evaluated through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Conclusion: The findings suggest that hypothyroidism, through altered plasma protein expression, particularly CXCL10, may contribute to the pathogenesis of IPF. This novel insight highlights the potential of CXCL10 as a therapeutic target in IPF, especially in patients with hypothyroidism. The study emphasizes the need for further research into the complex interplay between autoimmune disorders and IPF, with a view towards developing targeted interventions for IPF management.

Assuntos

Quimiocina CXCL10 , Hipotireoidismo , Fibrose Pulmonar Idiopática , População Branca , Humanos , Quimiocina CXCL10/genética , Predisposição Genética para Doença , Hipotireoidismo/genética , Fibrose Pulmonar Idiopática/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , População Branca/genética

RESUMO

BACKGROUND: There is a close clinical association between hypothyroidism and nephrotic syndrome (NS) was close, but whether there is genetic causality between the two is not known. OBJECTIVE: Using pooled data from a genome-wide association study (GWAS), the association between hypothyroidism and NS was explored via Mendelian randomization (MR) analysis. METHODS: Single-nucleotide polymorphisms (SNPs) associated with hypothyroidism (or NS) were screened as genetic instrumental variables (IVs) from pooled GWAS data, and inverse-variance weighting (IVW) was used for the main analysis to estimate causal effects, with MR-Egger, weighted median, and weighted mode used as complementary methods. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out, were also conducted to assess the robustness of the results. RESULTS: Genetically predicted hypothyroidism was positively associated with the risk of developing NS (IVW: OR = 1.18, 95% CI: 1.07-1.30, p = 0.00; MR-Egger: OR = 1.36, 95% CI: 1.10-1.68, p = 0.01), and the MR-Egger intercept (intercept = -0.02, p = 0.14), MR-PRESSO test (p = 0.14), Cochran's Q test (p = 0.15) and leave-one-out test results supported the robustness of the results. Genetically predicted NS status might not be associated with an increased risk of developing hypothyroidism (IVW: OR = 1.01, 95% CI: 1.00-1.03, p = 0.08; MR-Egger: OR = 1.01, 95% CI: 0.98-1.04, p = 0.43), and the MR-Egger intercept (intercept < 0.01, p = 0.69), MR-PRESSO test (p = 0.64), Cochran's Q test (p = 0.61) and leave-one-out test results supported the robustness of the results. CONCLUSION: Hypothyroidism status could increase the risk of developing NS.

Assuntos

Estudo de Associação Genômica Ampla , Hipotireoidismo , Análise da Randomização Mendeliana , Síndrome Nefrótica , Polimorfismo de Nucleotídeo Único , Humanos , Hipotireoidismo/genética , Hipotireoidismo/complicações , Síndrome Nefrótica/genética , Síndrome Nefrótica/complicações , Predisposição Genética para Doença , Fatores de Risco

RESUMO

While circulating metabolites and immune system have been increasingly linked to hypothyroidism risk, the causality underlying these associations remains largely uninterrogated. We used Mendelian randomization to identified putative causal traits for hypothyroidism via integrating omics data. Briefly, we utilized 1180 plasma metabolites and 731 immune cells traits as exposures to identify putatively causal traits for hypothyroidism in the discovery (40,926 cases) and replication cohorts (14,871 cases). By combining MR results from two large-scale cohorts, we ultimately identified 21 putatively causal traits, including five plasma metabolites and 16 immune cell traits. CD3 on CD28+ CD4+ T cell and 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (p-16:0/18:1) demonstrated the most pronounced positive and negative associations with hypothyroidism risk, respectively. The odds ratio and 95% confidence interval were 1.09 (1.07, 1.12) and 0.81 (0.75, 0.87), respectively. No evidence of horizontal pleiotropy, heterogeneity among instrumental variables or reverse causation were found for these 21 significant associations. Our study elucidates key metabolites and immune cell traits associated with hypothyroidism. These findings provide new insights into the etiology and potential therapeutic targets for hypothyroidism.

Assuntos

Hipotireoidismo , Hipotireoidismo/metabolismo , Hipotireoidismo/genética , Humanos , Análise da Randomização Mendeliana , Masculino , Feminino , Metabolômica , Multiômica

RESUMO

Biallelic loss-of-function variants in the IYD gene cause hypothyroidism resulting from iodine wasting. We describe 8 patients (from 4 families in which the parents are first cousins) who are homozygous for a variant in IYD (including a novel missense deleterious variant, c.791C>T [P264L], in 1 family). Seven patients presented between 5 and 16 years of age with a large goiter, overt hypothyroidism, and a high serum thyroglobulin. The goiter subsided with levothyroxine therapy in most. Upon stopping levothyroxine in 5 patients, goiter and hypothyroidism reappeared in 3. In these 3 patients, a rising serum thyroglobulin concentration preceded hypothyroidism and goiter and urinary iodine excretion was low. In patients who remained euthyroid, urinary iodine was normal. In conclusion, these patients bearing biallelic pathogenic variants in IYD developed a large goiter, a high serum thyroglobulin, and overt hypothyroidism when their iodine intake was low.

Assuntos

Bócio , Hipotireoidismo , Linhagem , Tiroxina , Humanos , Feminino , Masculino , Adolescente , Hipotireoidismo/genética , Criança , Pré-Escolar , Tiroxina/uso terapêutico , Bócio/genética , Tireoglobulina/genética , Iodo/deficiência , Alelos , Mutação de Sentido Incorreto , Simportadores

RESUMO

OBJECTIVE: The aim of the study is to map the shared genetic component and relationships between thyroid and reproductive health traits to improve the understanding of the interplay between those domains. DESIGN: A large-scale genetic analysis of thyroid traits (hyper- and hypothyroidism, and thyroid-stimulating hormone levels) was conducted in up to 743 088 individuals of European ancestry from various cohorts. METHODS: We evaluated genetic associations using genome-wide association study (GWAS) meta-analysis, GWAS Catalog lookup, gene prioritization, mouse phenotype lookup, and genetic correlation analysis. RESULTS: GWAS meta-analysis results for thyroid phenotypes showed that 50 lead variants out of 253 (including 5/52 of the novel hits) were linked to reproductive health in previous literature. Genetic correlation analyses revealed significant correlations between hypothyroidism and reproductive phenotypes. The results showed that 31.9% of thyroid-associated genes also had an impact on reproductive phenotypes, with the most affected functions being related to genitourinary tract issues. CONCLUSIONS: The study discovers novel genetic loci linked to thyroid phenotypes and highlights the shared genetic determinants between thyroid function and reproductive health, providing evidence for the genetic pleiotropy and shared biological mechanisms between these traits in both sexes.

Assuntos

Estudo de Associação Genômica Ampla , Saúde Reprodutiva , Doenças da Glândula Tireoide , Humanos , Feminino , Masculino , Doenças da Glândula Tireoide/genética , Animais , Fenótipo , Hipotireoidismo/genética , Camundongos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Tireotropina/sangue , Hipertireoidismo/genética

Assuntos

Proteínas Proto-Oncogênicas c-ret , Humanos , Feminino , Criança , Proteínas Proto-Oncogênicas c-ret/genética , Anormalidades Múltiplas/genética , Tiroxina/uso terapêutico , Hipotireoidismo/genética , Hipotireoidismo/tratamento farmacológico , Puberdade Precoce/genética , Mutação , Heterozigoto

RESUMO

Hypothyroidism and subclinical hypothyroidism were both characterized by elevated levels of thyroid stimulating hormone (TSH). Previous studies had found that high iodine or hyperlipidemia alone was associated with increased TSH level. However, their combined effects on TSH have not been elucidated. In this study, combination of high iodine and hyperlipidemia was established through the combined exposure of high-water iodine and high fat diet in Wistar rats. The results showed that combined exposure of high iodine and high fat can induce higher TSH level. The mRNA and protein levels of sodium iodide transporters (NIS) and type 1 deiodinase (D1) in thyroid tissues, which were crucial genes in the synthesis of thyroid hormones, decreased remarkably in combined exposure group. Mechanistically, down-regulated long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) may regulate the expression of NIS by increasing miR-339-5p, and regulating D1 by increasing miR-224-5p. Then, the above findings were explored in subjects exposed to high water iodine and hyperlipidemia. The results indicated that in population combined with high iodine and hyperlipidemia, TSH level increased to higher level and lncRNA MALAT1-miR-339-5p-NIS axis was obviously activated. Collectively, this study found that combined exposure of high iodine and hyperlipidemia induced a higher level of TSH, and lncRNA MALAT1-miR-339-5p-NIS axis may play important role.

Assuntos

Hiperlipidemias , Iodo , MicroRNAs , RNA Longo não Codificante , Ratos Wistar , Tireotropina , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Tireotropina/sangue , Tireotropina/metabolismo , Hiperlipidemias/metabolismo , Hiperlipidemias/genética , Masculino , Glândula Tireoide/metabolismo , Glândula Tireoide/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ratos , Simportadores/genética , Simportadores/metabolismo , Humanos , Hipotireoidismo/metabolismo , Hipotireoidismo/genética , Hipotireoidismo/induzido quimicamente , Iodeto Peroxidase/metabolismo , Iodeto Peroxidase/genética

RESUMO

BACKGROUND AND PURPOSE: Subclinical hypothyroidism (SCH) has been identified to be associated with implantation failure, in which the dysfunction of trophoblast cells is involved. In this study, the transcriptomics of aborted placenta from SCH rats were analyzed. Jupiter microtubule-associated homolog 2 (JPT2) was downregulated in the aborted placenta. This study aims to investigate its role in SCH-associated miscarriage. METHODS: Spontaneous abortion was observed in SCH rats generated by thyroidectomy combined with levothyroxine administration. The transcriptomics analysis was performed using aborted placenta. Afterward, the effects of JPT2 on trophoblast cells were explored using gain-and loss-of-function experiments. RESULTS: Transcriptomics analysis showed 1286 downregulated genes and 2300 upregulated genes in the aborted placenta, and JPT2 was significantly downregulated in the aborted placenta from SCH rats. Afterward, gain-and loss-of-function experiments exhibited that overexpression of JPT2 promoted the proliferation, migration, invasion, spheroid formation of HTR-8/SVneo trophoblast cells and their attachment to endometrial stromal cells, while these biological behaviors were suppressed by JPT2 knockdown. Furthermore, JPT2 accelerated the transcription of leptin receptor (LEPR), and activated signal transducer and activator of transcription 3 (STAT3) signal in a transcription factor AP-2γ-dependent manner. In addition, silencing of LEPR abolished the role of JPT2. CONCLUSION: Our results revealed that JPT2, which was downregulated in the aborted placenta from SCH rats, promoted proliferation, migration, invasion, spheroid formation, and attachment of trophoblast cells via regulating LEPR/STAT3 axis as a transcription co-factor. It is indicated that low expression of JPT2 may contribute to the abortion in individuals with SCH.

Assuntos

Aborto Espontâneo , Hipotireoidismo , Fator de Transcrição STAT3 , Feminino , Animais , Hipotireoidismo/metabolismo , Hipotireoidismo/genética , Hipotireoidismo/patologia , Ratos , Gravidez , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Aborto Espontâneo/metabolismo , Aborto Espontâneo/genética , Aborto Espontâneo/etiologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologia , Placenta/metabolismo , Ratos Sprague-Dawley , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Humanos , Proliferação de Células , Transdução de Sinais

RESUMO

The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet the causal direction remains unclear. This study aimed to investigate the potential causal relationship between TDFDs and the risk of developing OP and related fractures. We obtained pooled data from genome-wide association studies (GWASs) conducted on TDFDs and OP in European populations and identified single-nucleotide polymorphisms (SNPs) with genome-wide significance levels associated with exposure to TDFDs as instrumental variables. Inverse variance weighted (IVW) was employed as the primary method for Mendelian randomization (MR) analysis, supplemented by MR‒Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were conducted to evaluate the robustness of the findings. The IVW method demonstrated an increased risk of OP in patients with TDFDs, including hyperthyroidism and hypothyroidism (TDFDs: OR = 1.11; 95% CI 1.09, 1.13; hypothyroidism: OR = 1.14; 95% CI 1.10, 1.17; hyperthyroidism: OR = 1.09; 95% CI 1.06, 1.12). These findings were supported by supplementary analysis, which revealed a positive correlation between TDFDs and the risk of OP. Multiple sensitivity analyses confirmed the absence of horizontal pleiotropy in the study, thus indicating the robustness of our results. The causal relationship between TDFDs and increased risk of OP implies the need for early bone mineral density (BMD) screening and proactive prevention and treatment strategies for individuals with TDFDs.

Assuntos

Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteoporose , Polimorfismo de Nucleotídeo Único , Humanos , Osteoporose/genética , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/epidemiologia , Hipertireoidismo/genética , Hipertireoidismo/complicações , Fatores de Risco , Hipotireoidismo/genética , Hipotireoidismo/epidemiologia

RESUMO

BACKGROUND: Numerous organs, including the thyroid gland, depend on vitamin D to function normally. Insufficient levels of serum 25-hydroxyvitamin D [25(OH)D] are seen as a potential factor contributing to the emergence of several thyroid disorders, however, the causal relationship remains unclear. Here we use a Mendelian randomization (MR) approach to investigate the causal effect of serum 25(OH)D concentration on the indicators of thyroid function. METHODS: We conducted a two-sample MR analysis utilizing summary data from the most extensive genome-wide association studies (GWAS) of serum 25(OH)D concentration (n = 443,734 and 417,580), thyroid-stimulating hormone (TSH, n = 271,040), free thyroxine (fT4, n = 119,120), free triiodothyronine (fT3, n = 59,061), total triiodothyronine (TT3, n = 15,829), as well as thyroid peroxidase antibody levels and positivity (TPOAb, n = 12,353 and n = 18,297), low TSH (n = 153,241), high TSH (n = 141,549), autoimmune hypothyroidism (n = 287,247) and autoimmune hyperthyroidism (n = 257,552). The primary analysis was conducted using the multiplicative random-effects inverse variance weighted (IVW) method. The weighted mode, weighted median, MR-Egger, MR-PRESSO, and Causal Analysis Using Summary Effect estimates (CAUSE) were used in the sensitivity analysis. RESULTS: The IVW, as well as MR Egger and CAUSE analysis, showed a suggestive causal effect of 25(OH)D concentration on high TSH. Each 1 SD increase in serum 25(OH)D concentration was associated with a 12% decrease in the risk of high TSH (p = 0.02). Additionally, in the MR Egger and CAUSE analysis, we found a suggestive causal effect of 25(OH)D concentration on autoimmune hypothyroidism. Specifically, each 1 SD increase in serum 25(OH)D concentration was associated with a 16.34% decrease in the risk of autoimmune hypothyroidism (p = 0.02). CONCLUSIONS: Our results support a suggestive causal effect which was negative in direction across all methods used, meaning that higher genetically predicted vitamin D concentration possibly lowers the odds of having high TSH or autoimmune hypothyroidism. Other thyroid parameters were not causally influenced by vitamin D serum concentration.

Assuntos

Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Glândula Tireoide , Tireotropina , Vitamina D , Humanos , Vitamina D/sangue , Vitamina D/análogos & derivados , Glândula Tireoide/metabolismo , Tireotropina/sangue , Testes de Função Tireóidea , Hipotireoidismo/genética , Hipotireoidismo/sangue , Tri-Iodotironina/sangue , Tiroxina/sangue , Hipertireoidismo/genética , Hipertireoidismo/sangue