{Reference Type}: Journal Article
{Title}: Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease.
{Author}: Yuan H;Liu Z;Chen M;Xu Q;Jiang Y;Zhang T;Suo C;Chen X;
{Journal}: BMC Med
{Volume}: 22
{Issue}: 1
{Year}: 2024 Jun 11
{Factor}: 11.15
{DOI}: 10.1186/s12916-024-03466-0
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.