Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Medical School, University of Western Australia, Crawley, WA, Australia.
J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2191-e2202. doi: 10.1210/clinem/dgaa975.
Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.
To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.
We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.
We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.
This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
循环游离三碘甲状腺原氨酸（fT3）、游离甲状腺素（fT4）和促甲状腺激素（TSH）的浓度部分是可遗传的特征。最近的研究提高了对其遗传结构的认识。表观遗传修饰，如 DNA 甲基化（DNAm），可能在垂体-甲状腺轴的调节和作用中很重要，但数据有限。
在来自 2 个澳大利亚队列的受试者中，鉴定 fT3、fT4 和 TSH 与基因组中差异甲基化位置（DMP）之间的新关联。
我们对来自布里斯班系统遗传学研究（中位年龄 14.2 岁，n=563）和雷因研究（中位年龄 17.0 岁，n=863）的参与者进行了甲状腺功能参数和 DNAm 的全基因组关联研究（EWAS）。通过免疫测定法测量血浆 fT3、fT4 和 TSH。使用 Illumina HumanMethylation450 BeadChip 阵列评估血液中的 DNAm 水平。分析采用广义线性混合模型来检验 DNAm 与甲状腺功能参数之间的关联。对来自 2 个队列的数据进行荟萃分析。
我们鉴定出与 TSH 具有全基因组显著关联（P<2.4E-7）的 2 个 DMPs 和与 fT3 具有关联的 6 个 DMPs，包括 KLF9 中的 cg00049440（P=2.88E-10）和 DOT1L 中的 cg04173586（P=2.09E-16），这两个基因都已知受 fT3 诱导。所有 DMPs 与 DNAm 和 TSH 呈正相关，与 DNAm 和 fT3 呈负相关。没有 DMPs 与 fT4 显著相关。我们鉴定出与 fT3、fT4 或 TSH 相关的 23 个差异甲基化区域。
本研究表明，血液中 DNAm 与 fT3 和 TSH 之间存在关联。这可能为甲状腺激素作用和/或垂体-甲状腺轴功能的机制提供了一些见解。
