DataSheet_1_Causal relationship between thyroid dysfunction and hallux valgus: A two-sample Mendelian randomization study.docx

IntroductionPrevious observational studies have reported that thyroid dysfunction is associated with hallux valgus (HV). However, the causal effect of thyroid dysfunction on hallux valgus is still unknown. To assess whether there is a causal relationship between thyroid dysfunction and hallux valgus, we performed a two-sample Mendelian randomization (MR) study.
MethodsThe data of the two-sample Mendelian randomization study were obtained from public databases. In this study, hypothyroidism, hyperthyroidism, free thyroxine (FT4), and thyrotropin (TSH) were chosen as exposures. The single nucleotide polymorphisms (SNP) of hypothyroidism and hyperthyroidism were from the genome-wide association studies (GWAS) of the IEU database, including 337,159 subjects. Data for FT4 and TSH (72,167 subjects) were extracted from the ThyroidOmics Consortium. HV was used as the outcome. The SNPs associated with HV were selected from a GWAS of 202,617 individuals in the fignngen database. The inverse variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including MR-presso, MR-Egger, and weighted median. In addition, Cochran’s Q test, MR-presso, MR-Egger regression, and the leave-one-out test were used as sensitivity analysis, and the MR-pleiotropy test was performed to examine pleiotropy.
ResultsAccording to the results of IVW, we found that there was a causal relationship between hypothyroidism and HV, and hypothyroidism increased the incidence of HV (OR = 2.838 (95% CI: 1.116–7.213); p = 0.028). There were no significant causal effects of hyperthyroidism, FT4, and TSH on HV (p > 0.05). Sensitivity analyses showed that the results were robust and reliable, and no horizontal pleiotropy was detected.
ConclusionsOur findings provided genetic support that hypothyroidism might increase the risk of HV. It will predict the occurrence of HV in patients with hypothyroidism and provide suggestions for early prevention and intervention.

引言：既往观察性研究已表明甲状腺功能异常与拇外翻（hallux valgus, HV）存在关联，但甲状腺功能异常对拇外翻的因果效应仍未明确。为探究甲状腺功能异常与拇外翻之间是否存在因果关联，本研究开展了两样本孟德尔随机化（two-sample Mendelian randomization, MR）研究。

方法：本研究的两样本孟德尔随机化分析数据均来自公共数据库。本研究选取甲状腺功能减退（hypothyroidism）、甲状腺功能亢进（hyperthyroidism）、游离甲状腺素（free thyroxine, FT4）以及促甲状腺素（thyrotropin, TSH）作为暴露因素。甲状腺功能减退与甲状腺功能亢进的单核苷酸多态性（single nucleotide polymorphisms, SNP）数据来自IEU数据库的全基因组关联研究（genome-wide association studies, GWAS），纳入受试者共337159名。游离甲状腺素与促甲状腺素的数据（纳入72167名受试者）则来自ThyroidOmics联盟。以拇外翻作为结局指标，其相关单核苷酸多态性选自fignngen数据库中一项纳入202617名个体的全基因组关联研究。本研究以逆方差加权（inverse variance weighted, IVW）法作为主要分析手段，同时采用4种补充分析方法，包括MR-presso、MR-Egger以及加权中位数法。此外，本研究采用Cochran Q检验、MR-presso、MR-Egger回归以及留一法检验进行敏感性分析，并通过MR多效性检验（MR-pleiotropy test）检测多效性。

结果：逆方差加权分析结果显示，甲状腺功能减退与拇外翻存在因果关联，且甲状腺功能减退会升高拇外翻的发病风险（比值比OR=2.838，95%置信区间CI：1.116~7.213；P=0.028）。甲状腺功能亢进、游离甲状腺素以及促甲状腺素对拇外翻均无显著因果效应（P>0.05）。敏感性分析结果表明本研究结论稳健可靠，未检测到水平多效性。

结论：本研究结果为甲状腺功能减退可能升高拇外翻发病风险提供了遗传学依据。该研究可为预测甲状腺功能减退患者的拇外翻发生风险提供参考，并为早期预防与干预提供指导建议。