Causal Association Between Serum Thyrotropin and Obesity: A Bidirectional, Mendelian Randomization Study

Wang, Xichang; Gao, Xiangjing; Han, Yutong; Zhang, Fan; Lin, Zheyu; Wang, Hong; Wang, Teng; Shan, Zhongyan

doi:10.1210/clinem/dgab183

“…Another MR analysis pointed out that TSH could be significantly elevated by the genetically driven BMI, while fT4 could not be affected by BMI [ 56 ]. Notice in our study, we used the latest and largest GWAS summary data, where fT4 cohorts included nearly 70000 participants.…”

Section: Discussionmentioning

confidence: 99%

Causal Association of Thyroid Signaling with C-Reactive Protein: A Bidirectional Mendelian Randomization

Li

¹

,

Geng

²

,

Wang

³

et al. 2022

Computational and Mathematical Methods in Medicine

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Context. Existing literature demonstrated that thyroid-stimulating hormone (TSH) and free thyroid hormone (fT4) were associated with the C-reactive protein (CRP), an inflammatory risk factor of cardiovascular diseases (CVD), but the causal relationship between them remained unclear. Methods. Based on the latest genome-wide association study summary data, bidirectional two-sample Mendelian randomization (MR) was employed to detect the causal relationship and effect direction between TSH, fT4, and CRP. Furthermore, in view of obesity being an important risk factor of CVD, obesity trait waist-hip ratio (WHR) and body mass index (BMI) were treated as the research objects in MR analyses for exploring the causal effects of TSH and fT4 on them, respectively. Results. Genetically increased CRP was associated with increased TSH ( β = − 0.02 , P = 0.011 ) and with increased fT4 ( β = 0.043 , P = 0.001 ), respectively, but there was no evidence that TSH or fT4 could affect CRP. In further analyses, genetically increased TSH was associated with decreased WHR ( β = − 0.02 , P = 3.99 e − 4 ). Genetically increased WHR was associated with decreased fT4 ( β = − 0.081 , P = 0.002 ). Genetically increased BMI was associated with increased TSH ( β = 0.03 , P = 0.028 ) and with decreased fT4 ( β = − 0.078 , P = 1.05 e − 4 ). Causal associations of WHR and BMI with thyroid signaling were not supported by weighted median analysis in sensitivity analyses. Conclusion. TSH and fT4 were increased due to the higher genetically predicted CRP. WHR was decreased due to the higher genetically predicted TSH. These findings will provide reference for the prevention and treatment of inflammation and metabolic syndrome.

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“…A P < 0.05 was defined as a threshold for statistical significance. The Bonferroni correction redefined the threshold for statistical significance in multiple testing (P < 0.05/n), where n refers to the number of MR tests ( 35 ). The adjusted P-values were 0.025 (0.05/2) for the forward MR analysis and 0.0125 (0.05/4) for the reverse MR analysis.…”

Section: Methodsmentioning

confidence: 99%

Iron status and obesity-related traits: A two-sample bidirectional Mendelian randomization study

Zhou

¹

,

Zhang²,

Chen³

et al. 2023

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BackgroundThe association between iron status and obesity-related traits is well established by observational studies, but the causality is uncertain. In this study, we performed a two-sample bidirectional Mendelian randomization analysis to investigate the causal link between iron status and obesity-related traits.MethodsThe genetic instruments strongly associated with body mass index (BMI), waist-hip ratio (WHR), serum ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity (TIBC) were obtained through a series of screening processes from summary data of genome-wide association studies (GWAS) of European individuals. We used numerous MR analytical methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, and maximum likelihood to make the conclusions more robust and credible, and alternate methods, including the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis to evaluate the horizontal pleiotropy and heterogeneities. In addition, the MR-PRESSO and RadialMR methods were utilized to identify and remove outliers, eventually achieving reduced heterogeneity and horizontal pleiotropy.ResultsThe results of IVW analysis indicated that genetically predicted BMI was associated with increased levels of serum ferritin (β: 0.077, 95% CI: 0.038, 0.116, P=1.18E-04) and decreased levels of serum iron (β: -0.066, 95% CI: -0.106, -0.026, P=0.001) and TSAT (β: -0.080, 95% CI: -0.124, -0.037, P=3.08E-04), but not associated with the levels of TIBC. However, the genetically predicted WHR was not associated with iron status. Genetically predicted iron status were not associated with BMI and WHR.ConclusionsIn European individuals, BMI may be the causative factor of serum ferritin, serum iron, and TSAT, but the iron status does not cause changes in BMI or WHR.

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“…This model was used to evaluate if the association of thyroid function with cardiovascular risk factors was independent of BMI and diabetes. Although thyroid hormones may influence BMI and the risk of diabetes, BMI and diabetes also significantly affect thyroid hormone levels and are potential confounders of the association of thyroid hormones with the cardiovascular risk ( 35 ). Models evaluating the association of thyroid function with anthropometric parameters did not include BMI; models evaluating the association of thyroid function with lipid profile and dyslipidemia were restricted to participants not treated with lipid-lowering drugs; and models evaluating the association with glucose profile were restricted to participants not treated with antidiabetic drugs.…”

Section: Methodsmentioning

confidence: 99%

Association of thyroid function, within the euthyroid range, with cardiovascular risk: The EPIPorto study

Fontes‐Carvalho

¹

,

Borges‐Canha

²

,

Leite

³

et al. 2022

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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.

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Causal Association Between Serum Thyrotropin and Obesity: A Bidirectional, Mendelian Randomization Study

Cited by 38 publications

References 48 publications

Causal Association of Thyroid Signaling with C-Reactive Protein: A Bidirectional Mendelian Randomization

Causal Association of Thyroid Signaling with C-Reactive Protein: A Bidirectional Mendelian Randomization

Iron status and obesity-related traits: A two-sample bidirectional Mendelian randomization study

Association of thyroid function, within the euthyroid range, with cardiovascular risk: The EPIPorto study

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