背景:以前的研究,包括孟德尔随机化(MR),已经证明2型糖尿病(T2D)和血糖特征与代谢功能障碍相关的脂肪变性肝病(MASLD)的风险增加有关。然而,很少有研究探索潜在的途径,如铁稳态的作用。
方法:我们使用两步MR方法来调查T2D的遗传易感性的关联,血糖性状,铁生物标志物,和肝脏疾病。我们分析了T2D的各种全基因组关联研究的汇总统计数据(n=933,970),血糖性状(n≤209,605),铁生物标志物(n≤246,139),MASLD(n≤972,707),和相关的生物标志物(丙氨酸氨基转移酶(ALT)和质子密度脂肪分数(PDFF))。我们的主要分析是基于方差逆加权,其次是一些敏感性分析。我们还进行了中介分析,并探讨了肝铁在事后分析中的作用。
结果:T2D的遗传倾向和空腹胰岛素(FI)升高可能会增加肝脏脂肪变性的风险(对T2D的倾向:患病率每增加一倍1.14,95%CI:1.10,1.19;ORFI:3.31/logpmol/l,95%CI:1.92,5.72)和相关生物标志物。T2D的责任也可能增加发展为肝硬化的风险。基因升高的铁蛋白,血清铁,和肝脏铁与肝脏脂肪变性的高风险相关(ORferritin:1.25/SD,95%CI1.07,1.46;奥利弗铁:每SD1.15,95%CI:1.05,1.26)和肝硬化(OR血清铁:1.31,95%CI:1.06,1.63;ORliver铁:1.34,95%CI:1.07,1.68)。铁蛋白部分介导FI和肝脏脂肪变性之间的关联(介导的比例:7%,95%CI:2-12%)。
结论:我们的研究为T2D和胰岛素升高在肝脏脂肪变性和肝硬化风险中的因果作用提供了可靠的证据,并表明铁蛋白可能在这种关联中起中介作用。
BACKGROUND: Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis.
METHODS: We used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis.
RESULTS: Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated
ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68).
Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2-12%).
CONCLUSIONS: Our
study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates
ferritin may play a mediating role in this association.