Whether thyroid dysfunction plays a causal role in the development of cancer remains inconclusive. We conducted a two‐sample Mendelian randomization study to investigate the associations between genetic predisposition to thyroid dysfunction and 22 site‐specific cancers. Single‐nucleotide polymorphisms associated with four traits of thyroid function were selected from a genome‐wide association meta‐analysis with up to 72,167 European‐descent individuals. Summary‐level data for breast cancer and 21 other cancers were extracted from the Breast Cancer Association Consortium (122,977 breast cancer cases and 105,974 controls) and UK Biobank (367,643 individuals). For breast cancer, a meta‐analysis was performed using data from both sources. Genetically predicted thyroid dysfunction was associated with breast cancer, with similar patterns of associations in the Breast Cancer Association Consortium and UK Biobank. The combined odds ratios of breast cancer were 0.94 (0.91–0.98; p = 0.007) per genetically predicted one standard deviation increase in TSH levels, 0.96 (0.91–1.00; p = 0.053) for genetic predisposition to hypothyroidism, 1.04 (1.01–1.07; p = 0.005) for genetic predisposition to hyperthyroidism and 1.07 (1.02–1.12; p = 0.003) per genetically predicted one standard deviation increase in free thyroxine levels. Genetically predicted TSH levels and hypothyroidism were inversely with thyroid cancer; the odds ratios were 0.47 (0.30–0.73; p = 0.001) and 0.70 (0.51–0.98; p = 0.038), respectively. Our study provides evidence of a causal association between thyroid dysfunction and breast cancer (mainly ER‐positive tumors) risk. The role of TSH and hypothyroidism for thyroid cancer and the associations between thyroid dysfunction and other cancers need further exploration.

中文翻译：

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甲状腺功能和功能障碍与整体乳腺癌和甲状腺癌的因果关系：两样本孟德尔随机化研究。


甲状腺功能障碍是否在癌症的发生中起因果作用仍无定论。我们进行了一项双样本孟德尔随机化研究，以调查甲状腺功能障碍的遗传易感性与 22 种部位特异性癌症之间的关联。与甲状腺功能四个特征相关的单核苷酸多态性是从对多达 72,167 名欧洲血统个体的全基因组关联荟萃分析中选出的。乳腺癌和其他 21 种癌症的概要级数据来自乳腺癌协会联盟（122,977 例乳腺癌病例和 105,974 例对照）和英国生物银行（367,643 例个体）。对于乳腺癌，使用两个来源的数据进行荟萃分析。基因预测的甲状腺功能障碍与乳腺癌相关，乳腺癌协会联盟和英国生物银行也有类似的关联模式。 TSH 水平每增加一个标准差，乳腺癌的综合优势比为 0.94 (0.91–0.98; p = 0.007)，甲状腺功能减退症遗传易感性为 0.96 (0.91–1.00; p = 0.053)，1.04 (1.01–1.07) ; p = 0.005）对于甲状腺功能亢进的遗传易感性和1.07（1.02-1.12; p = 0.003）每遗传预测游离甲状腺素水平增加一个标准偏差。基因预测的 TSH 水平和甲状腺功能减退与甲状腺癌呈反比；比值比分别为 0.47 (0.30–0.73; p = 0.001) 和 0.70 (0.51–0.98; p = 0.038)。我们的研究提供了甲状腺功能障碍与乳腺癌（主要是 ER 阳性肿瘤）风险之间存在因果关系的证据。 TSH 和甲状腺功能减退症在甲状腺癌中的作用以及甲状腺功能障碍与其他癌症之间的关联需要进一步探索。