DataSheet_1_Hypothyroidism has a protective causal association with hepatocellular carcinoma: A two-sample Mendelian randomization study.pdf

ObjectiveObservational studies suggest an association between hypothyroidism and the risk of hepatocellular carcinoma (HCC), but the causality and direction of these effects are still inconclusive. We aim to test whether hypothyroidism is causally associated with the risk of HCC by using Mendelian randomization (MR) analysis.MethodsSingle-nucleotide polymorphisms (SNPs) associated with hypothyroidism were screened via a genome-wide association study (GWAS) on 337,159 individuals of European descent (16,376 cases and 320,783 controls). The SNPs associated with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were selected from a GWAS of 72,167 individuals of European descent. Summary-level data for HCC (168 cases and 372,016 controls) were extracted from UK Biobank. An inverse-variance-weighted (IVW) method was used as the primary MR analysis. Sensitivity analyses were examined via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. The assumption that exposure causes outcome was verified using the MR Steiger test.ResultsTwo-Sample MR analysis showed inverse associations between genetically predicted hypothyroidism and HCC risk (OR = 0.997, 95% CI, 0.995-0.999; P = 0.016). There were no statistical indications of heterogeneity among instruments (P-het = 0.667). Across five MR methods, genetically predicted hypothyroidism shows a consistent correlation with HCC. The leave-one-out analysis indicated that no single SNP changed the overall estimate (P = 0.016). In addition, the MR Steiger test revealed that hypothyroidism was causal for HCC and not the opposite (P = 0.000). Finally, there was no evidence for a direct causal effect of TSH level and FT4 level on HCC risk.ConclusionOur results provide some that genetically determined hypothyroidism decreases the risk of HCC, although the size of the causal estimate is small. Further research is required to comprehend the mechanisms underlying this putative causative association, and follow-up clinical trials need to be conducted to establish whether inducing hypothyroidism could be beneficial for patients who are suffering from HCC. During future treatment of hypothyroidism, close attention to liver function may also be required to prevent a possible increased risk of HCC.

观察性研究表明，甲状腺功能减退症与肝细胞癌（HCC）的风险之间存在关联，但因果关系的方向尚无定论。本研究旨在通过孟德尔随机化（MR）分析，检验甲状腺功能减退症是否与HCC风险存在因果关系。方法：通过针对337,159名欧洲血统个体（其中16,376例病例和320,783名对照）的全基因组关联研究（GWAS）筛选出与甲状腺功能减退症相关的单核苷酸多态性（SNPs）。从针对72,167名欧洲血统个体的GWAS中选取了与促甲状腺激素（TSH）和游离甲状腺素（FT4）相关的SNPs。从英国生物样本库中提取了肝细胞癌（HCC）的汇总水平数据（168例病例和372,016名对照）。主要采用逆方差加权（IVW）方法进行MR分析。通过MR-Egger回归、异质性检验、多效性检验和留一法敏感性检验进行了敏感性分析。使用MR Steiger检验验证了暴露导致结果的假设。结果：双样本MR分析显示，遗传预测的甲状腺功能减退症与HCC风险呈负相关（OR = 0.997，95% CI，0.995-0.999；P = 0.016）。工具变量之间不存在统计学上的异质性（P-het = 0.667）。在五种MR方法中，遗传预测的甲状腺功能减退症与HCC均表现出一致的关联。留一法分析表明，没有单个SNPs改变总体估计值（P = 0.016）。此外，MR Steiger检验揭示，甲状腺功能减退症是HCC的因果因素，而非反之（P = 0.000）。最后，没有证据表明TSH水平和FT4水平对HCC风险有直接的因果效应。结论：我们的结果表明，由遗传决定的甲状腺功能减退症降低了HCC的风险，尽管因果估计值的大小较小。需要进一步研究以理解这种潜在的因果关联背后的机制，并需开展后续的临床试验以确定诱导甲状腺功能减退症是否对患有HCC的患者有益。在未来治疗甲状腺功能减退症的过程中，密切注意肝功能也是必要的，以防止可能增加的HCC风险。