State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China.
Department of Epidemiology, School of Public Health, Fudan University, No. 130 Dongan Road, Shanghai, 200032, China.
BMC Med. 2024 Jun 11;22(1):239. doi: 10.1186/s12916-024-03466-0.
Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored.
We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality.
96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e - 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15-6.85), 2.82-fold (1.69-4.72), and 4.41-fold (3.04-6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome.
Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions.
线粒体（MT）功能障碍是肝脏疾病的一个标志。然而，MT 相关基因中的功能变体（如蛋白截断变体 [PTV]）对肝脏疾病风险的影响尚未得到广泛探讨。
我们使用来自英国生物库的 442603 名参与者的全外显子组测序数据，提取了 2466 个 MT 相关核基因中的 60928 个 PTV。我们研究了它们与肝脏相关生物标志物所代表的肝功能障碍以及慢性肝病和与肝脏相关的死亡率风险之间的关系。
在总共 442603 名参与者中，有 96.10%的人携带至少一个 PTV。我们鉴定出了 866 个与肝功能障碍显著相关的 PTV（P 值<8.21e-07）。这些 PTV 的编码基因主要富集在与脂质、脂肪酸、氨基酸和碳水化合物代谢相关的途径中。在 1.07%（4721）的参与者中存在 866 个 PTV。与不携带任何 PTV 的参与者相比，携带者患纤维化和肝硬化、肝癌和与肝脏疾病相关的死亡率的风险分别增加了 5.33 倍（95%CI 4.15-6.85）、2.82 倍（1.69-4.72）和 4.41 倍（3.04-6.41）。这些不良影响在基于年龄、性别、体重指数、吸烟状况以及高血压、糖尿病、血脂异常和代谢综合征的亚组中是一致的。
我们的研究结果表明，MT 相关基因中的 PTV 对肝脏疾病风险有显著影响，这突显了这些变体在识别易患肝脏疾病的人群和促进早期临床干预方面的重要性。
