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Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders.

ABSTRACT: BACKGROUND:The thyroid plays a key role in development and homeostasis, but it has been difficult to establish causality with diseases and phenotypic traits because of several potential confounders. METHODS:To determine the causal effect of euthyroid function, we conducted a two-sample Mendelian randomization study of euthyroid thyrotropin (TSH) and free thyroxine (FT4) levels with respect to 2419 traits assessed in 337,199 individuals from UK Biobank. Additionally, we investigated the molecular differences between hypothyroidism and hyperthyroidism using genome-wide data. RESULTS:After multiple testing correction, sixteen traits appear to be affected by genetically-determined euthyroid TSH, including multiple thyroid-related traits, e.g., hypothyroidism (p = 2.39 × 10-17), height (p = 2.76 × 10-10), body fat distribution (impedance of whole body, p = 4.43 × 10-8), pulse rate (p = 2.84 × 10-8), female infertility (p = 4.91 × 10-6), and hearing aid use (p = 7.10 × 10-5). Moreover, we found a consistent genetic correlation between hypothyroidism and hyperthyroidism (rg = 0.45, p = 5.45 × 10-6) with several immune pathways shared between these diseases. Two molecular pathways survived multiple testing correction for specificity to hyperthyroidism, JAK/STAT signaling (p = 1.02 × 10-6) and Rac guanyl-nucleotide exchange factor activity (p = 4.39 × 10-6). CONCLUSION:Our data shed new light on the inter-individual variability of euthyroid function and the molecular mechanisms of the two thyroid disorders investigated.

SUBMITTER: Ravera S

PROVIDER: S-EPMC6210201 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders.

Ravera Silvia S Carrasco Nancy N Gelernter Joel J Polimanti Renato R

Journal of clinical medicine 20180921 10

<h4>Background</h4>The thyroid plays a key role in development and homeostasis, but it has been difficult to establish causality with diseases and phenotypic traits because of several potential confounders.<h4>Methods</h4>To determine the causal effect of euthyroid function, we conducted a two-sample Mendelian randomization study of euthyroid thyrotropin (TSH) and free thyroxine (FT4) levels with respect to 2419 traits assessed in 337,199 individuals from UK Biobank. Additionally, we investigate ...[more]

PMID: 30248900

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Project description:BackgroundPrevious studies have reported a negative relationship between thyroid-stimulating hormone (TSH) and renal function in euthyroid individuals, but others have found that higher free thyroxine (FT4) was associated with an increased risk of chronic kidney disease. This study was designed to analyze the relationship between thyroid and renal function from a new perspective of sensitivity to thyroid hormone.MethodsThis retrospective study included 2831 euthyroid individuals who underwent a health examination at the First Hospital of China Medical University between January 2017 and December 2018. Parametric Thyroid Feedback Quantile-based Index (PTFQIFT4), TSH index (TSHI), thyrotroph T4 resistance index (TT4RI), free triiodothyronine to FT4 ratio (FT3/FT4), the secretory capacity of the thyroid gland (SPINA-GT) and the sum activity of peripheral deiodinases (SPINA-GD) were calculated. We also innovated the TT3RI and PTFQIFT3 indices based on FT3 and TSH. Renal function was assessed by estimated glomerular filtration rate (eGFR) CKD-EPI and creatinine-cystatin C-KDIGO equations.ResultsAfter adjustment of basic characteristics and comorbidities, linear regression showed that eGFR CKD-EPI was positively associated with FT3/FT4 (β = 23.31), and inversely correlated to PTFQI FT4 (β= -2.69) (both p < .001). When comparing the fourth versus the first quartile of PTFQI FT4, the odds ratio (OR) for a reduced renal function was 1.89 (95% CI 1.28-2.80), and the OR was 0.64 (95% CI 0.43-0.95) when comparing quartiles of FT3/FT4 (both p for trend< .05). In addition, for every 1SD increase in PTFQI FT4, the OR for a reduced renal function was 1.27 (95%CI 1.10-1.47). TSHI, TT4RI and TT3RI also showed a negative correlation to renal function. Similar results were obtained in SPINA-GD as in FT3/FT4.ConclusionsIn euthyroid individuals, decreased sensitivity to thyroid hormone is associated with reduced renal function. The composite PTFQIFT4 index correlates more strongly to renal function than TSH or T4 alone.KEY MESSAGESDecreased sensitivity to thyroid hormone is associated with reduced renal function in the euthyroid population.The recently developed composite index PTFQIFT4 seems to correlate more strongly to renal function than individual TSH or FT4 parameters.Innovative indices TT3RI and PTFQIFT3 based on the interaction between T3 and TSH may also reflect sensitivity to thyroid hormone.

Project description:BackgroundThyroid hormones are important modulators of cardiovascular function. Both hypothyroidism and hyperthyroidism are known to contribute to an increased cardiovascular risk. It remains uncertain whether thyroid hormones level within the euthyroid range are associated with cardiometabolic risk. We aimed to evaluate the association between thyroid function levels within the euthyroid range and cardiovascular risk in a population-based cohort.MethodsEight hundred thirty-five subjects aged ≥45 years from the EPIPorto population-based cohort were included. We excluded participants with TSH, free T4 (FT4), or free T3 (FT3) outside of the reference range, or with previous cardiovascular or thyroid disease. The associations between thyroid function, cardiovascular risk factors and the 10-year estimated risk of cardiovascular events (using SCORE2 and SCORE2-OP) were evaluated in linear and logistic regression models, crudely and adjusting for age, sex, BMI, diabetes, and smoking.ResultsThe mean age of the participants was 61.5 (SD 10.5) years and 38.9% were men. Eleven percent of the participants had diabetes, 47.8% had dyslipidemia, and 54.8% had hypertension. The mean body mass index (BMI) was 27.4 (SD 4.6) kg/m2, and the median (percentile25-75) 10-year risk of cardiovascular events was 5.46% (2.92, 10.11). Participants with higher BMI, larger waist circumference and higher hs-CRP had higher levels of FT3 and FT3/FT4 ratio. Lower FT3/FT4 ratio and higher FT4 levels were associated with higher prevalence of diabetes and more adverse lipid profile. Higher TSH, lower FT3 and lower FT3/FT4 ratio were associated with lower eGFR. Lower FT3, lower FT3/FT4 ratio and higher FT4 were associated with an increased 10-year risk of cardiovascular events.ConclusionsIn a population-based study, variations of thyroid function within the euthyroid range were associated with cardiovascular risk factors. On one hand, individuals with higher BMI, larger waist circumference and higher hs-CRP had higher levels of FT3 and FT3/FT4 ratio. On the other hand, a decreased conversion of T4 to T3 (lower FT3, lower FT3/FT4 ratio and/or higher FT4) was associated with a higher prevalence of diabetes, a more adverse lipid profile, a lower eGFR and an increased 10-year risk of cardiovascular events.

Project description:Thyroid cancer in humans has a fast-growing prevalence, with the most common lethal endocrine malignancy for unknown reasons. The current study was aimed to perform qualitative and quantitative investigation and characterization of the gut bacterial composition of euthyroid thyroid cancer patients. The fecal samples were collected from sixteen euthyroid thyroid cancer patients and ten from healthy subjects. The PCR-DGGE was conducted by targetting the V3 region of 16S rRNA gene, as well as real-time PCR for Bacteroides vulgatus, E.coli Bifidobacterium, Clostridium leptum and Lactobacillus were carried. High-throughput sequencing of V3+V4 region of 16S rRNA gene was performed on Hiseq 2500 platform on 20 (10 healthy & 10 diseased subjects) randomly selected fecal samples. The richness indices and comparative diversity analysis showed significant gut microbial modification in euthyroid thyroid cancer than control. At phylum level, there was significant enrichment of Firmicutes, Verrucomicrobia, while a significant decrease in Bacteroidetes was detected in the experimental group. At family statistics, significant high levels of Ruminococcaceae and Verrucomicrobiaceae, while the significant lower abundance of Bacteroidaceae, Prevotellaceae, Porphyromonadaceae, and Alcaligenaceae was after observed. It also found that the significantly raised level of Escherichia-Shigella, Akkermansia [Eubacterium]_coprostanoligenes, Dorea, Subdoligranulum, and Ruminococcus_2 genera, while significantly lowered genera of the patient group were Prevotella_9, Bacteroides and Klebsiella. The species-level gut microbial composition showed a significantly raised level of Escherichia coli in euthyroid thyroid cancer. Thus, this study reveals that euthyroid thyroid cancer patients have significant gut microbial dysbiosis. Moreover, Statistics (P<0.05) of each gut microbial taxa were significantly changed in euthyroid thyroid cancer patients. Therefore, the current study may propose new approaches to understanding thyroid cancer patients' disease pathways, mechanisms, and treatment.

Project description:Objective and designWe explored the cross-sectional and longitudinal associations of thyroid function within the normal range with cardiovascular disease (CVD) risk factors and adiposity measures.Patients and measurementsA total of 3483 (50·4% women) participants for the cross-sectional CVD study and 1630 (41·2% women) participants for the cross-sectional body composition substudy were drawn from the Framingham Third Generation Exam 1; 2912 participants (50·1% women) for the longitudinal CVD study and 713 participants (35·9% women) for the longitudinal body composition substudy were drawn from the Framingham Third Generation Exams 1-2. Thyroid function was assessed by thyrotropin [thyroid-stimulating hormone (TSH)] and free thyroxine (fT4) concentrations within the reference range at Exam 1. The associations between thyroid function and CVD risk factors were modelled via multivariable-adjusted regression models. Multivariable adjustment included age, sex, current smoking, postmenopausal status and BMI.ResultsCross-sectionally, higher TSH concentration was associated with increased odds of hypertriglyceridaemia [odds ratio (OR)=1·10], and higher BMI (β = 0·19 kg/m2 ), total cholesterol (β = 0·05 mmol/l), triglycerides (β = 0·0006 mmol/l) and subcutaneous adipose tissue (SAT) volume (β = 38·8 cm3 ) (all P < 0·05). Cross-sectionally, fT4 was inversely associated with metabolic and adiposity-related CVD risk factors, including obesity (OR = 1·17), hypertriglyceridaemia (OR = 1·09), BMI (β = 0·42 kg/m2 ), total cholesterol (β = 0·05 mmol/l), triglycerides (β = 0·0002 mmol/l), visceral adipose tissue (VAT) volume (β = -20·7 cm3 ) and attenuation (0·17 HU) and VAT/SAT ratio (β = -0·01) (all P < 0·05). However, during 6·1 years of follow-up, baseline TSH and fT4 levels were not longitudinally associated with CVD risk factors and adiposity measures.ConclusionsThyroid function within the normal range is cross-sectionally, but not longitudinally, associated with CVD risk factors and adiposity measures.

Project description:IntroductionThe relationship between thyroid function/homeostasis parameters and renal function has been extensively studied. However, the relationship between thyroid function and thyroid homeostasis parameters with albuminuria among elderly individuals remains unclear.MethodsThe population was divided into an albuminuria group and a non-albuminuria group for baseline characteristic difference analysis. Multivariable logistic regression was used to test the association between thyroid function, and thyroid homeostasis parameters and albuminuria. The nonlinear relationship was explored with restricted cubic splines. Meanwhile, we investigated whether the relationship also existed in the diabetes and hypertension subgroups. Receiver operating characteristic (ROC) curves were used to assess the effectiveness of the indices.ResultsFT4 and TFQIFT4 were positively correlated with albuminuria (OR = 1.12; 95% CI = 1.02-1.23, p = 0.02; OR = 1.79; 95% CI = 1.08-2.99, p = 0.03), and FT3/FT4 was negatively correlated with albuminuria (OR = 0.03; 95% CI = 0.00-0.26, p = 0.003). Additionally, the nonlinear relationship between FT3/FT4 as well as TSHI and albuminuria was approximately U-shaped. Similar results were observed in the hypertension subgroup but not in the diabetes subgroup. There was a U-shaped nonlinear relationship between FT3 and albuminuria in the diabetes group. In addition, FT3/FT4 performed better than TFQI, TT4RI, and TSHI in ROC analyses for albuminuria prediction.ConclusionFT4, TFQIFT4, and a low FT3/FT4 ratio were risk factors for albuminuria in euthyroid individuals over 60 years old. However, FT3 was more associated with albuminuria in the diabetes subgroup. TSH was not associated with albuminuria in any analysis. In our study, we attempted to provide more reasonable thyroid parameters and basis for evaluating patients with underlying albuminuria. FT3/FT4 may be used as a helpful indicator to predict albuminuria and provide novel ideas for the evaluation and treatment of albuminuria.

Dataset Information

Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders.

Publications

Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders.

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