Mendelian Randomization Highlights the Causal Role of Normal Thyroid Function on Blood Lipid Profiles

Wang, Yanjun; Guo, Ping; Liu, Lu; Zhang, Yanan; Zeng, Ping; Yuan, Zhongshang

doi:10.1210/endocr/bqab037

Cited by 15 publications

(14 citation statements)

References 69 publications

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“…In the colocalization analysis, there was little evidence that 2 traits showing evidence of a causal association in the MR analysis were colocalized, which suggested that the SNPs in the gene locus might be LD with proxied variants and might not be suitable for perturbing drug targets, or that multiple causal variants might exist within the given region, which was not suitable for colocalization analysis ( 22 ). Meanwhile, the value of PP.H1 was relatively high, indicating variants in the region were significantly associated with resistin and were unlikely to affect the outcome, thus obeying the MR main assumption and further supporting our MR estimates ( 45 ). Because of the limited summary-level statistics for chemerin and RBP4, colocalization analysis was not performed on the causal associations between chemerin and CAD, RBP4 and HF.…”

Section: Discussionsupporting

confidence: 82%

Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Chen

Zhang

Yidilisi

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Observational studies have suggested associations between adipokines and cardiovascular disease (CVD), but the roles of certain adipokines remain controversial, and these associations have not yet been ascertained causally. Objective To investigate whether circulating adipokines causally affect the risk of CVD using two-sample Mendelian randomization (MR). Methods Independent genetic variants strongly associated with adiponectin, resistin, chemerin and retinol binding protein 4 (RBP4) were selected from public genome-wide association studies. Summary-level statistics for CVD, including coronary artery disease (CAD), myocardial infarction, atrial fibrillation (AF), heart failure (HF), stroke and its subtypes were collected. The inverse-variance weighted and Wald ratio methods were used for the MR estimates. The MR-PRESSO, weighted median, MR-Egger, leave-one-out analysis, MR Steiger and colocalization analysis were used in the sensitivity analysis. Results Genetically predicted resistin levels were positively associated with AF risk (OR 1.09; 95% CI, 1.04 to 1.13; P = 4.1×10 -5), which was attenuated to null after adjusting for blood pressure. We observed suggestive associations between higher genetically predicted chemerin levels and an increased risk of CAD (OR 1.27; 95% CI, 1.01 to 1.60; P = 0.040), higher genetically predicted RBP4 levels and an increased risk of HF (OR 1.14; 95% CI, 1.02 to 1.27; P = 0.024). There was no causal association between genetically predicted adiponectin levels and CVD risk. Conclusions Our findings reveal the causal association between resistin and AF, probably acting through blood pressure, and suggest potential causal associations between chemerin and CAD, RBP4 and HF.

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Section: Discussionsupporting

confidence: 82%

Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Chen

Zhang

Yidilisi

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…They explored the genetic association between TSH and serum lipid profiles via Mendelian randomization (MR). According to Wang et al 17 , per 1 standard deviation (SD) increase in normal TSH was significantly associated with a 0.048 SD increase in TC and a 0.032 SD increase in LDL-C, whereas TSH did not show a causal association with HDL-C and TGs. The study by van Vliet et al 18 unveiled a positive association between high TSH within normal range with the levels of very low-density lipoprotein subclasses and components, TGs, and the TG contents in lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

Age-specific serum thyrotropin reference range for the diagnosis of subclinical hypothyroidism and its association with lipid profiles in the elderly population

Zhang

Wang

et al. 2022

Sci Rep

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The overdiagnosis of subclinical hypothyroidism (SCH) in the elderly has driven researchers to establish age-specific thyroid stimulating hormone (TSH) intervals to precisely evaluate the prevalence of SCH. Moreover, abnormal lipid profiles, an insidious manifestation of SCH, show various impacts on different age groups. This study aimed to establish an age-specific TSH reference range to clarify the spectrum of SCH in the elderly. The prevalence of dyslipidemia and the age-specific association between TSH and lipid profiles were analyzed to elucidate the relationship between SCH and dyslipidemia. This cross-sectional study enrolled 2460 participants aged ≥ 65 years via cluster sampling. All participants received physical, laboratory tests and thyroid ultrasound examination and completed the questionnaire. The chi-square test was used to analyze variations of dyslipidemia prevalence among different groups. The Cochran-Armitage trend test was applied for testing the linear trends of age-specific prevalence of dyslipidemia among different TSH intervals in each age group. After adjusting for confounding factors, the age-specific association between TSH and lipid profiles was identified using multi-variate linear regression analysis. The TSH reference ranges in the 65–70 age group, 71–80 age group and > 80 age group were 0.65–5.51 mIU/L, 0.85–5.89 mIU/L and 0.78–6.70 mIU/L, respectively. Using these age-specific reference ranges, the prevalence of SCH in the whole population was 3.74%, which was significantly lower than the prevalence based on the laboratory reference range (10.28%). In the 65–70 age group, only the prevalence of high total cholesterol (TC) increased significantly with the age-specific TSH intervals, and TSH was positively associated with TC and low-density lipoprotein cholesterol (LDL-C). In the 71–80 and > 80 age groups, the prevalence of high TC, high triglycerides (TGs), and high LDL-C increased significantly with elevated TSH reference ranges. The levels of TC, TGs, and LDL-C were also positively associated with TSH level in 71–80 age group. However, such an association disappeared in > 80 age group. An age-specific reference range for TSH can effectively prevent the overdiagnosis of SCH in the elderly. Aging could somewhat attenuate the impact of TSH on lipid profiles.

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“…MR is established on the basis that if a causal relationship exists between PBC and thyroid dysfunction, the SNP related to PBC will also be related to thyroid dysfunction through the occurrence of PBC, in which case the IVs only associate with PBC, and MR can help establish a causal relationship between PBC and thyroid function (Davey Smith and Hemani, 2014). Also, two-sample MR has been used to explore the causal relationship between thyroid function and breast cancer (Yuan et al, 2020), atrial fibrillation (Ellervik et al, 2019), and blood lipid profile (Wang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study

et al. 2021

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Background: Primary biliary cholangitis (PBC) is an autoimmune disease and is often accompanied by thyroid dysfunction. Understanding the potential causal relationship between PBC and thyroid dysfunction is helpful to explore the pathogenesis of PBC and to develop strategies for the prevention and treatment of PBC and its complications.Methods: We used a two-sample Mendelian randomization (MR) method to estimate the potential causal effect of PBC on the risk of autoimmune thyroid disease (AITD), thyroid-stimulating hormone (TSH) and free thyroxine (FT4), hyperthyroidism, hypothyroidism, and thyroid cancer (TC) in the European population. We collected seven datasets of PBC and related traits to perform a series MR analysis and performed extensive sensitivity analyses to ensure the reliability of our results.Results: Using a sensitivity analysis, we found that PBC was a risk factor for AITD, TSH, hypothyroidism, and TC with odds ratio (OR) of 1.002 (95% CI: 1.000–1.005, p = 0.042), 1.016 (95% CI: 1.006–1.027, p = 0.002), 1.068 (95% CI: 1.022–1.115, p = 0.003), and 1.106 (95% CI: 1.019–1.120, p = 0.042), respectively. Interestingly, using reverse-direction MR analysis, we also found that AITD had a significant potential causal association with PBC with an OR of 0.021 (p = 5.10E−4) and that the other two had no significant causal relation on PBC.Conclusion: PBC causes thyroid dysfunction, specifically as AITD, mild hypothyroidism, and TC. The potential causal relationship between PBC and thyroid dysfunction provides a new direction for the etiology of PBC.

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Mendelian Randomization Highlights the Causal Role of Normal Thyroid Function on Blood Lipid Profiles

Cited by 15 publications

References 69 publications

Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Age-specific serum thyrotropin reference range for the diagnosis of subclinical hypothyroidism and its association with lipid profiles in the elderly population

The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study

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