School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
School of Public Health and Health Policy, City University of New York, New York, NY, USA.
Int J Epidemiol. 2023 Dec 25;52(6):1914-1925. doi: 10.1093/ije/dyad093.
Mendelian randomization (MR) studies show iron positively associated with type 2 diabetes (T2D) but included potentially biasing hereditary haemochromatosis variants and did not assess reverse causality.
We assessed the relation of iron homeostasis with T2D and glycaemic traits bidirectionally, using genome-wide association studies (GWAS) of iron homeostasis biomarkers [ferritin, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT) (n ≤ 246 139)], T2D (DIAMANTE n = 933 970 and FinnGen n = 300 483), and glycaemic traits [fasting glucose (FG), 2-h glucose, glycated haemoglobin (HbA1c) and fasting insulin (FI) (n ≤ 209 605)]. Inverse variance weighting (IVW) was the main analysis, supplemented with sensitivity analyses and assessment of mediation by hepcidin.
Iron homeostasis biomarkers were largely unrelated to T2D, although serum iron was potentially associated with higher T2D [odds ratio: 1.07 per standard deviation; 95% confidence interval (CI): 0.99 to 1.16; P-value: 0.078) in DIAMANTE only. Higher ferritin, serum iron, TSAT and lower TIBC likely decreased HbA1c, but were not associated with other glycaemic traits. Liability to T2D likely increased TIBC (0.03 per log odds; 95% CI: 0.01 to 0.05; P-value: 0.005), FI likely increased ferritin (0.29 per log pmol/L; 95% CI: 0.12 to 0.47; P-value: 8.72 x 10-4). FG likely increased serum iron (0.06 per mmol/L; 95% CI: 0.001 to 0.12; P-value: 0.046). Hepcidin did not mediate these associations.
It is unlikely that ferritin, TSAT and TIBC cause T2D although an association for serum iron could not be excluded. Glycaemic traits and liability to T2D may affect iron homeostasis, but mediation by hepcidin is unlikely. Corresponding mechanistic studies are warranted.
孟德尔随机化（MR）研究表明，铁与 2 型糖尿病（T2D）呈正相关，但纳入的遗传性血色素沉着症变体可能存在偏倚，并且没有评估反向因果关系。
我们使用铁稳态生物标志物[铁蛋白、血清铁、总铁结合能力（TIBC）、转铁蛋白饱和度（TSAT）]（n≤246139）、T2D（DIAMANTE n=933970 和 FinnGen n=300483）和血糖特征[空腹血糖（FG）、2 小时血糖、糖化血红蛋白（HbA1c）和空腹胰岛素（FI）]（n≤209605）的全基因组关联研究（GWAS），双向评估铁稳态与 T2D 和血糖特征的关系。主要分析采用逆方差加权（IVW），并辅以敏感性分析和铁调素介导作用的评估。
铁稳态生物标志物与 T2D 相关性不大，尽管血清铁可能与 T2D 升高相关[优势比：DIAMANTE 中每标准差增加 1.07；95%置信区间（CI）：0.99 至 1.16；P 值：0.078]。较高的铁蛋白、血清铁、TSAT 和较低的 TIBC 可能降低 HbA1c，但与其他血糖特征无关。T2D 的易感性可能增加 TIBC（每对数几率增加 0.03；95%CI：0.01 至 0.05；P 值：0.005），FI 可能增加铁蛋白（每对数 pmol/L 增加 0.29；95%CI：0.12 至 0.47；P 值：8.72 x 10-4）。FG 可能增加血清铁（每 mmol/L 增加 0.06；95%CI：0.001 至 0.12；P 值：0.046）。铁调素不太可能介导这些关联。
尽管不能排除血清铁存在关联，但铁蛋白、TSAT 和 TIBC 不太可能导致 T2D。血糖特征和 T2D 的易感性可能会影响铁稳态，但不太可能通过铁调素来介导。需要进行相应的机制研究。
