RESUMEN

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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hipertiroidismo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sepsis , Humanos , Sepsis/genética , Sepsis/complicaciones , Hipertiroidismo/genética , Hipertiroidismo/complicaciones , Hipotiroidismo/genética , Factores de Riesgo , Enfermedades de la Tiroides/genética

RESUMEN

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.

Asunto(s)

Enfermedades Cardiovasculares , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Tiroxina , Humanos , Hipotiroidismo/diagnóstico , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Tiroxina/uso terapéutico , Medición de Riesgo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Terapia de Reemplazo de Hormonas/efectos adversos , Factores de Riesgo , Fenotipo , Femenino , Infarto del Miocardio/genética , Infarto del Miocardio/epidemiología , Infarto del Miocardio/diagnóstico , Polimorfismo de Nucleótido Simple , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Masculino , Variantes Farmacogenómicas , Factores de Riesgo de Enfermedad Cardiaca

RESUMEN

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.

Asunto(s)

Bursitis , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Bursitis/genética , Bursitis/epidemiología , Predisposición Genética a la Enfermedad

RESUMEN

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.

Asunto(s)

Bocio , Hipotiroidismo , Linaje , Tiroxina , Humanos , Femenino , Masculino , Adolescente , Hipotiroidismo/genética , Niño , Preescolar , Tiroxina/uso terapéutico , Bocio/genética , Tiroglobulina/genética , Yodo/deficiencia , Alelos , Mutación Missense , Simportadores

RESUMEN

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.

Asunto(s)

Quimiocina CXCL10 , Hipotiroidismo , Fibrosis Pulmonar Idiopática , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Población Blanca , Humanos , Fibrosis Pulmonar Idiopática/genética , Quimiocina CXCL10/genética , Hipotiroidismo/genética , Población Blanca/genética , Predisposición Genética a la Enfermedad

RESUMEN

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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Síndrome Nefrótico , Polimorfismo de Nucleótido Simple , Humanos , Hipotiroidismo/genética , Hipotiroidismo/complicaciones , Síndrome Nefrótico/genética , Síndrome Nefrótico/complicaciones , Predisposición Genética a la Enfermedad , Factores de Riesgo

RESUMEN

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.

Asunto(s)

Hipotiroidismo , Hipotiroidismo/metabolismo , Hipotiroidismo/genética , Humanos , Análisis de la Aleatorización Mendeliana , Masculino , Femenino , Metabolómica , Multiómica

RESUMEN

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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Salud Reproductiva , Enfermedades de la Tiroides , Humanos , Femenino , Masculino , Enfermedades de la Tiroides/genética , Animales , Fenotipo , Hipotiroidismo/genética , Ratones , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Tirotropina/sangre , Hipertiroidismo/genética

Asunto(s)

Proteínas Proto-Oncogénicas c-ret , Humanos , Femenino , Niño , Proteínas Proto-Oncogénicas c-ret/genética , Anomalías Múltiples/genética , Tiroxina/uso terapéutico , Hipotiroidismo/genética , Hipotiroidismo/tratamiento farmacológico , Pubertad Precoz/genética , Mutación , Heterocigoto

RESUMEN

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.

Asunto(s)

Hiperlipidemias , Yodo , MicroARNs , ARN Largo no Codificante , Ratas Wistar , Tirotropina , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , MicroARNs/metabolismo , MicroARNs/genética , Tirotropina/sangre , Tirotropina/metabolismo , Hiperlipidemias/metabolismo , Hiperlipidemias/genética , Masculino , Glándula Tiroides/metabolismo , Glándula Tiroides/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Ratas , Simportadores/genética , Simportadores/metabolismo , Humanos , Hipotiroidismo/metabolismo , Hipotiroidismo/genética , Hipotiroidismo/inducido químicamente , Yoduro Peroxidasa/metabolismo , Yoduro Peroxidasa/genética

RESUMEN

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.

Asunto(s)

Aborto Espontáneo , Hipotiroidismo , Factor de Transcripción STAT3 , Femenino , Animales , Hipotiroidismo/metabolismo , Hipotiroidismo/genética , Hipotiroidismo/patología , Ratas , Embarazo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Aborto Espontáneo/metabolismo , Aborto Espontáneo/genética , Aborto Espontáneo/etiología , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patología , Placenta/metabolismo , Ratas Sprague-Dawley , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Humanos , Proliferación Celular , Transducción de Señal

RESUMEN

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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Glándula Tiroides , Tirotropina , Vitamina D , Humanos , Vitamina D/sangre , Vitamina D/análogos & derivados , Glándula Tiroides/metabolismo , Tirotropina/sangre , Pruebas de Función de la Tiroides , Hipotiroidismo/genética , Hipotiroidismo/sangre , Triyodotironina/sangre , Tiroxina/sangre , Hipertiroidismo/genética , Hipertiroidismo/sangre

RESUMEN

Background: Epidemiologic studies have suggested co-morbidity between hypothyroidism and psychiatric disorders. However, the shared genetic etiology and causal relationship between them remain currently unclear. Methods: We assessed the genetic correlations between hypothyroidism and psychiatric disorders [anxiety disorders (ANX), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP)] using summary association statistics from genome-wide association studies (GWAS). Two disease-associated pleiotropic risk loci and genes were identified, and pathway enrichment, tissue enrichment, and other analyses were performed to determine their specific functions. Furthermore, we explored the causal relationship between them through Mendelian randomization (MR) analysis. Results: We found significant genetic correlations between hypothyroidism with ANX, SCZ, and MDD, both in the Linkage disequilibrium score regression (LDSC) approach and the high-definition likelihood (HDL) approach. Meanwhile, the strongest correlation was observed between hypothyroidism and MDD (LDSC: rg=0.264, P=7.35×10-12; HDL: rg=0.304, P=4.14×10-17). We also determined a significant genetic correlation between MDD with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels. A total of 30 pleiotropic risk loci were identified between hypothyroidism and psychiatric disorders, of which the 15q14 locus was identified in both ANX and SCZ (P values are 6.59×10-11 and 2.10×10-12, respectively) and the 6p22.1 locus was identified in both MDD and SCZ (P values are 1.05×10-8 and 5.75×10-14, respectively). Sixteen pleiotropic risk loci were identified between MDD and indicators of thyroid function, of which, four loci associated with MDD (1p32.3, 6p22.1, 10q21.1, 11q13.4) were identified in both FT4 normal level and Hypothyroidism. Further, 79 pleiotropic genes were identified using Magma gene analysis (P<0.05/18776 = 2.66×10-6). Tissue-specific enrichment analysis revealed that these genes were highly enriched into six brain-related tissues. The pathway analysis mainly involved nucleosome assembly and lipoprotein particles. Finally, our two-sample MR analysis showed a significant causal effect of MDD on the increased risk of hypothyroidism, and BIP may reduce TSH normal levels. Conclusions: Our findings not only provided evidence of a shared genetic etiology between hypothyroidism and psychiatric disorders, but also provided insights into the causal relationships and biological mechanisms that underlie their relationship. These findings contribute to a better understanding of the pleiotropy between hypothyroidism and psychiatric disorders, while having important implications for intervention and treatment goals for these disorders.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Trastornos Mentales , Humanos , Hipotiroidismo/genética , Trastornos Mentales/genética , Trastornos Mentales/epidemiología , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Trastorno Bipolar/genética , Trastorno Depresivo Mayor/genética , Desequilibrio de Ligamiento , Trastornos de Ansiedad/genética

RESUMEN

Background: Gastric cancer (GC) is the third leading cause of cancer death worldwide, and hypothyroidism has been identified as a potential influencing factor. Despite known associations between hypothyroidism and various cancers, the causal link between hypothyroidism and GC and potential mediators of this relationship remains unclear. This study aimed to clarify these relationships using Mendelian randomization (MR). Methods: Utilizing genetic variant information from the FinnGen and MRC Integrative Epidemiology Unit open genome-wide association studies (GWAS) databases, we conducted univariable and multivariable MR analyses to explore the causal relationship between hypothyroidism and GC risk. The analysis was adjusted for confounders such as BMI, smoking status, and alcohol intake, and included mediator MR analysis to examine the role of high cholesterol. Results: We identified a significant inverse association between hypothyroidism and GC risk (OR = 0.93, 95% CI= 0.89-0.98, P = 0.003), with no evidence of reverse causation or pleiotropy. Adjustments for Helicobacter pylori infection weakened this association. Mediator analysis highlighted high cholesterol levels, chronic hepatitis B infection, and diabetes/endocrine disease status as significant mediators of the protective effect of hypothyroidism on GC risk. Conclusion: Our findings suggest that hypothyroidism may confer a protective effect against GC, mediated in part by high cholesterol and other factors. These results underscore the importance of thyroid function and metabolic health in GC risk, offering new insights for preventive strategies and highlighting the need for further research into these complex associations.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de Mediación , Análisis de la Aleatorización Mendeliana , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiología , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Hipotiroidismo/complicaciones , Factores de Riesgo , Femenino , Masculino , Polimorfismo de Nucleótido Simple

RESUMEN

The link between celiac disease (CeD) and thyroid dysfunction has been investigated. However, it is uncertain if CeD is causally linked to thyroid dysfunction. A 2-sample Mendelian randomization study was conducted to ascertain the causal connection between CeD and thyroid dysfunction. Using data from the FinnGen Consortium, a 2-sample Mendelian randomization study was conducted to look at the connection between thyroid dysfunction and CeD. Another replication of the data from the UK Biobank was subsequently performed to confirm our findings. Furthermore, a sequence of sensitivity analyses was performed. The inverse variance weighting technique demonstrates that genetically determined CeD is substantially linked with hypothyroidism, thyrotoxicosis, Graves' disease, and free thyroxine. However, no significant associations were found between CeD and thyroid-stimulating hormone or thyroiditis. Moreover, we achieve the same results in duplicate datasets, which increases the reliability of our findings. This study suggests that CeD and thyroid dysfunction are linked, and it gives theoretical support and new ways of thinking about how to diagnose and treat both conditions.

Asunto(s)

Enfermedad Celíaca , Análisis de la Aleatorización Mendeliana , Enfermedades de la Tiroides , Humanos , Enfermedad Celíaca/genética , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/epidemiología , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/epidemiología , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Tirotropina/sangre

RESUMEN

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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoporosis , Polimorfismo de Nucleótido Simple , Humanos , Osteoporosis/genética , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/epidemiología , Hipertiroidismo/genética , Hipertiroidismo/complicaciones , Factores de Riesgo , Hipotiroidismo/genética , Hipotiroidismo/epidemiología

RESUMEN

PURPOSE: Observational studies and clinical validation have suggested a link between thyroid dysfunction and an elevated ovarian cancer (OC) risk. However, whether this association indicates a cause-and-effect relationship remains uncertain. We aimed to investigate the plausible causal impact of thyroid dysfunction on OC through a Mendelian randomization (MR) study. METHODS: Genome-wide association study (GWAS) data for thyrotropin (TSH), free thyroxine (FT4), hypothyroidism, and hyperthyroidism were obtained as exposures and those for OC (N = 199,741) were selected as outcomes. Inverse variance-weighted method was used as the main estimation method. A series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept analysis, forest plot scatter plot, and leave-one-out test, was conducted to assess the robustness of the estimates. RESULTS: Genetic prediction of hyperthyroidism was associated with a potential increase in OC risk (odds ratio = 1.094, 95% confidence interval: 1.029-1.164, p = 0.004). However, no evidence of causal effects of hypothyroidism, TSH, and FT4 on OC or reverse causality was detected. Sensitivity analyses demonstrated consistent and reliable results, with no significant estimates of heterogeneity or pleiotropy. CONCLUSIONS: This study employed MR to establish a correlation between hyperthyroidism and OC risk. By genetically predicting OC risk in patients with hyperthyroidism, our research suggests new insights for early prevention and intervention of OC.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hipertiroidismo , Análisis de la Aleatorización Mendeliana , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/sangre , Hipertiroidismo/genética , Hipertiroidismo/complicaciones , Tirotropina/sangre , Hipotiroidismo/genética , Polimorfismo de Nucleótido Simple , Tiroxina/sangre , Factores de Riesgo , Predisposición Genética a la Enfermedad

RESUMEN

Backgroud: Gastric cancer is one of the most common cancers worldwide, and its development is associated with a variety of factors. Previous observational studies have reported that thyroid dysfunction is associated with the development of gastric cancer. However, the exact relationship between the two is currently unclear. We used a two-sample Mendelian randomization (MR) study to reveal the causal relationship between thyroid dysfunction and gastric cancer for future clinical work. Materials and methods: This study is based on a two-sample Mendelian randomization design, and all data are from public GWAS databases. We selected hyperthyroidism, hypothyroidism, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) as exposures, with gastric cancer as the outcome. We used three statistical methods, namely Inverse-variance weighted (IVW), MR-Egger, and weighted median, to assess the causal relationship between thyroid dysfunction and gastric cancer. The Cochran's Q test was used to assess the heterogeneity among SNPs in the IVW analysis results, and MR-PRESSO was employed to identify and remove IVs with heterogeneity from the analysis results. MR-Egger is a weighted linear regression model, and the magnitude of its intercept can be used to assess the horizontal pleiotropy among IVs. Finally, the data were visualized through the leave-one-out sensitivity test to evaluate the influence of individual SNPs on the overall causal effect. Funnel plots were used to assess the symmetry of the selected SNPs, forest plots were used to evaluate the confidence and heterogeneity of the incidental estimates, and scatter plots were used to assess the exposure-outcome relationship. All results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). P<0.05 represents statistical significance. Results: According to IVW analysis, there was a causal relationship between hypothyroidism and gastric cancer, and hypothyroidism could reduce the risk of gastric cancer (OR=0.936 (95% CI:0.893-0.980), P=0.006).This means that having hypothyroidism is a protective factor against stomach cancer. This finding suggests that hypothyroidism may be associated with a reduced risk of gastric cancer.Meanwhile, there was no causal relationship between hyperthyroidism, FT4, and TSH and gastric cancer. Conclusions: In this study, we found a causal relationship between hypothyroidism and gastric cancer with the help of a two-sample Mendelian randomisation study, and hypothyroidism may be associated with a reduced risk of gastric cancer, however, the exact mechanism is still unclear. This finding provides a new idea for the study of the etiology and pathogenesis of gastric cancer, and our results need to be further confirmed by more basic experiments in the future.

Asunto(s)

Análisis de la Aleatorización Mendeliana , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/epidemiología , Humanos , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/epidemiología , Enfermedades de la Tiroides/complicaciones , Tirotropina/sangre , Hipertiroidismo/genética , Hipertiroidismo/complicaciones , Hipertiroidismo/epidemiología , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Factores de Riesgo , Causalidad

RESUMEN

Objective: Hypothyroidism, characterized by reduced thyroid hormone levels, and endometrial cancer, a prevalent gynecological malignancy, have been suggested to have a potential association in previous observational studies. However, the causal relationship between them remains uncertain. This study aimed to investigate the causal relationship between hypothyroidism and endometrial cancer using a bilateral Mendelian randomization approach. Methods: A bidirectional two-sample Mendelian randomization study was conducted using summary statistics from genome-wide association studies to identify genetic variants associated with hypothyroidism and endometrial cancer. The inverse variance weighting method was used as the main analysis, and sensitivity analyses were conducted to validate the MR results. Results: The results of our analysis did not support a causal effect of hypothyroidism (OR: 0.93, p=0.08) or autoimmune hypothyroidism (OR: 0.98, p=0.39) on endometrial cancer risk. In the reverse MR analysis, we did not find a significant causal effect of endometrial cancer on hypothyroidism (OR: 0.96, p=0.75) or autoimmune hypothyroidism (OR: 0.92, p=0.50). Based on subgroup analysis by pathological subtypes of endometrial cancer, the above findings were further substantiated (all p-value >0.05). Conclusions: Our Mendelian randomization analysis suggests a lack of causal association between hypothyroidism and endometrial cancer. To gain a deeper understanding of this association, it is essential to conduct large-scale randomized controlled trials in the future to validate our findings.

Asunto(s)

Neoplasias Endometriales , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/epidemiología , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Polimorfismo de Nucleótido Simple , Factores de Riesgo

RESUMEN

Background: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). The aim of this study was to determine in vivo which TH receptor (TR)-α or ß-and which mode of TR action-canonical gene expression or DNA-binding independent noncanonical action-mediate these effects. Methods: We compared global TRα and TRß knockout mice (TRαKO; TRßKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRßGS). Hearts were studied with echocardiography at baseline and after 7 weeks of T3 treatment. Gene expression was measured with real-time polymerase chain reaction. Heart rate was recorded with radiotelemetry transmitters for 7 weeks in untreated, hypothyroid, and T3-treated mice. Results: T3 induced ventricular hypertrophy in WT and TRßKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRß could compensate for absence of TRα. Conclusions: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRß could substitute for canonical but not noncanonical TRα action.

Asunto(s)

Cardiomegalia , Frecuencia Cardíaca , Ratones Noqueados , Receptores alfa de Hormona Tiroidea , Receptores beta de Hormona Tiroidea , Triyodotironina , Animales , Masculino , Ratones , Cardiomegalia/metabolismo , Cardiomegalia/genética , Hipotiroidismo/metabolismo , Hipotiroidismo/genética , Isoformas de Proteínas/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/metabolismo