Association between thyroid function levels and phenotypes associated with sarcopenia

doi:10.12307/2025.289

Abstract

Abstract:
BACKGROUND: Several observational studies have found a close relationship between thyroid function levels and sarcopenia, but the causal relationship between thyroid function levels and the onset of sarcopenia is not yet clear.
OBJECTIVE: To investigate the causal relationship between thyroid function levels and sarcopenia using a two sample Mendelian randomization method.
METHODS: A two sample Mendelian randomization analysis was conducted using genome-wide association study data on thyrotropin, free triiodothyronine, free tetraiodothyronine, subclinical hyperthyroidism, subclinical hypothyroidism, and four related phenotypes of sarcopenia - left hand grip strength, right hand grip strength, limb lean mass, and gait speed. The inverse-variance weighted method, weighted median method, simple mode method, weighted median estimator method, and MR Egger regression method were used as analysis methods, while heterogeneity test, pleiotropy test, MR-PRESSO, leave-one-out method, funnel plot and other methods were used for sensitivity analysis.
RESULTS AND CONCLUSION: Elevated levels of thyroid-stimulating hormone increased left- (β=0.02, SE=0.01, P=0.01) and right-handed grip strength (β=0.02, SE=0.01, P=0.01), an increase in free triiodothyronine decreased left- (β=-0.06, SE=0.02, P=9.5×10-5) and right-handed grip strength (β=-0.07, SE=0.02, P=9.3×10-5), and subclinical hyperthyroidism decreased gait speed (β=-4.4×10-3, SE=1.7×10-3, P=0.01). The sensitivity analysis results were basically consistent with the main analysis results. To conclude, an increase in thyroid-stimulating hormone is a protective factor for sarcopenia, and elevation of free triiodothyronine and subclinical hyperthyroidism may increase the risk of sarcopenia.

Key words: Mendelian randomization, causal relationship, thyroid function level, thyroid-stimulating hormone, free triiodothyronine, sarcopenia

CLC Number:

Li Jiatong, Jin Yue, Liu Runjia, Song Bowen, Zhu Xiaoqian, Li Nianhu . Association between thyroid function levels and phenotypes associated with sarcopenia[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(6): 1312-1320.

Figures/Tables 7

2.1 工具变量在经过显著相关、去除连锁不平衡、计算F值筛选及调整等位基因情况后，最终纳入与促甲状腺激素相关的单核苷酸多态性164个，与游离三碘甲状腺原氨酸相关的单核苷酸多态性17个，与游离四碘甲状腺原氨酸相关的单核苷酸多态性58个，与亚临床甲状腺功能亢进症相关的单核苷酸多态性28个，与亚临床甲状腺功能减退症相关的单核苷酸多态性11个。在利用这些单核苷酸多态性与结局相关联时，分别丢失了4，0，2，0，0个单核苷酸多态性。 2.2 甲状腺功能指标对肌少症相关特征表型的影响基于逆方差加权法的结果，提示促甲状腺激素对左手、右手握力存在较为显著的潜在因果效应(β=0.02，SE=0.01，P=0.01)，游离三碘甲状腺原氨酸对左手握力(β=-0.06，SE=0.02，P=9.5×10-5) 、右手握力(β=-0.07，SE=0.02，P=9.3×10-5)存在较为显著的潜在因果效应。同时用其他4种方法来确认结果的稳健性，其中加权中位数法、简单模式法和加权中值法的分析结果支持促甲状腺激素与左手握力相关，加权中位数法和加权中值法的分析结果支持促甲状腺激素与右手握力相关，加权中位数法、简单模式法和加权中值法的分析结果支持游离三碘甲状腺原氨酸与左手、右手握力相关，虽然MR-Egger等方法不支持该结论，但5种统计方法结果总效应值的方向一致，呈正相关，见表2。此外，MR-PRESSO方法在异常值校正前后的因果估计是一致的，散点图同样显示了5个方法的回归线基本一致，见图2。以上表明孟德尔随机化分析的结果是可靠的。孟德尔随机化分析并未发现促甲状腺激素与四肢瘦体质量、步速；游离三碘甲状腺原氨酸与四肢瘦体质量；游离四碘甲状腺原氨酸与握力、四肢瘦体质量、步速等肌少症相关表型间的显著关联。 2.3 两种亚临床甲状腺功能障碍疾病对肌少症相关特征表型的影响逆方差加权法结果显示，基因预测亚临床甲状腺功能亢进症对步速(β=-4.4×10-3，SE=1.7×10-3，P=0.01)存在较为显著的潜在因果效应。同时用其他4种方法来确认结果的稳健性，均支持亚临床甲状腺功能亢进症与步速指标相关，5种统计方法结果总效应值的方向一致，呈负相关，见表3。MR-PRESSO方法在异常值校正前后的因果估计是一致的，散点图同样显示了5个方法的回归线基本一致，见图3。结果并未发现亚临床甲状腺功能亢进症与左手握力、右手握力、四肢瘦体质量，亚临床甲状腺功能减退症与左手握力、右手握力、四肢瘦体质量、步速等肌少症相关表型间的显著关联。 2.4 敏感性分析基因预测游离三碘甲状腺原氨酸对步速(β=-0.02，SE=0.01，P=0.02)存在较为显著的潜在因果效应，但MR-Egger-intercept结果P < 0.05，存在一定的水平多效性。这意味着用于孟德尔随机化分析的工具变量可能通过暴露以外的路径影响结局，可靠性不足。对于其他指标MR-Egger-intercept分析未检测到潜在的水平多效性(促甲状腺激素对左手握力：P=0.60；促甲状腺激素对右手握力：P=0.37；游离三碘甲状腺原氨酸对左手握力：P=0.98；游离三碘甲状腺原氨酸对右手握力：P=0.68；亚临床甲状腺功能亢进症对步速：P=0.70)，说明工具变量并不显著通过暴露以外的途径影响结局。Cochran’s Q异质性检验发现了一定的异质性，但采用逆方差加权法随机效应模型并考虑核心假设2中的水平多效性检验，确保了分析结果的可靠性，见表4。"

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