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Cited by 3Genetic Associations and EpidemiologyMitochondrial Function and PathologyGenomics and Rare Diseases

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Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease

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Yuan, Huangbo, Liu, Zhenqiu, Chen, Mingyang, Xu, Qiaoyi, Jiang, Yanfeng, Zhang, Tiejun, Suo, Chen, Chen, Xingdong·2024·BMC Medicine
DOI 10.1186/s12916-024-03466-0PMC PMC11167739
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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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Fig. 1 Study design. WES, whole-exome sequencing data; MT, mitochondrial; PTV, protein truncating variant; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin; ALB, albumin
Fig. 1 Study design. WES, whole-exome sequencing data; MT, mitochondrial; PTV, protein truncating variant; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin; ALB, albuminCC BY · PubMed Central
Fig. 2 Chromosomal ideograms plot for coding genes of MT-related PTVs linked to liver-related biomarkers. An ideogram of all 22 chromosomes is plotted, along with the X chromosome. Lines are plotted on the chromosomes corresponding to the start location of each coding gene of PTV that was associated with liver-related biomarkers, and the line connects to colored circles representing the biomarkers associated with that PTV. Abbreviations: MT, mitochondrial; PTVs, protein truncating variants; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin; ALB, albumin
Fig. 2 Chromosomal ideograms plot for coding genes of MT-related PTVs linked to liver-related biomarkers. An ideogram of all 22 chromosomes is plotted, along with the X chromosome. Lines are plotted on the chromosomes corresponding to the start location of each coding gene of PTV that was associated with liver-related biomarkers, and the line connects to colored circles representing the biomarkers associated with that PTV. Abbreviations: MT, mitochondrial; PTVs, protein truncating variants; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin; ALB, albuminCC BY · PubMed Central
Fig. 3 Functional enrichment analysis of PTVs linked to liver-related biomarkers. A The top 15 pathways of Kyoto Encyclopedia of Genes and Genomes pathway analysis (KEGG) based on PTVs linking to liver-related biomarkers. The top 15 terminologies of biological process (BP) (B), cellular component (CC) (C), and molecular function (MF) (D) in gene ontology (GO) analysis based on PTVs linked to liver-related biomarkers. Abbreviations: MT, mitochondrial; NADP, nicotinamide adenine dinucleotide phosphate
Fig. 3 Functional enrichment analysis of PTVs linked to liver-related biomarkers. A The top 15 pathways of Kyoto Encyclopedia of Genes and Genomes pathway analysis (KEGG) based on PTVs linking to liver-related biomarkers. The top 15 terminologies of biological process (BP) (B), cellular component (CC) (C), and molecular function (MF) (D) in gene ontology (GO) analysis based on PTVs linked to liver-related biomarkers. Abbreviations: MT, mitochondrial; NADP, nicotinamide adenine dinucleotide phosphateCC BY · PubMed Central
Fig. 4 Cumulative incidences of liver diseases between mitochondrial-related PTV carriers and non-PTV carriers. Kaplan–Meier curves showing that mitochondrial-related PTV carriers had significantly increased risk of fibrosis and cirrhosis of liver (A), liver cancer (B), and liver disease-related mortality (C) when compared with non-PTV carriers
Fig. 4 Cumulative incidences of liver diseases between mitochondrial-related PTV carriers and non-PTV carriers. Kaplan–Meier curves showing that mitochondrial-related PTV carriers had significantly increased risk of fibrosis and cirrhosis of liver (A), liver cancer (B), and liver disease-related mortality (C) when compared with non-PTV carriersCC BY · PubMed Central
Fig. 5 Impact of mitochondrial-related PTVs on the risks of end-stage liver diseases and liver-related mortality. The impact of PTVs on the risk of end-stage liver diseases (fibrosis and cirrhosis of liver and liver cancer) and liver disease-related mortality was evaluated using a COX regression model. The model was adjusted for age, sex, alcohol intake frequency, ever smoked, physical activity level, education deprivation score, household income, BMI, hypertension, diabetes, and dyslipidemia. The incidence rates (per 100,000 person-years, /10^5pys) of diseases were also calculated in the whole population and subgroups. Abbreviations: PTV, protein truncating variant; HR, hazard ratio; CI, confidence interval
Fig. 5 Impact of mitochondrial-related PTVs on the risks of end-stage liver diseases and liver-related mortality. The impact of PTVs on the risk of end-stage liver diseases (fibrosis and cirrhosis of liver and liver cancer) and liver disease-related mortality was evaluated using a COX regression model. The model was adjusted for age, sex, alcohol intake frequency, ever smoked, physical activity level, education deprivation score, household income, BMI, hypertension, diabetes, and dyslipidemia. The incidence rates (per 100,000 person-years, /10^5pys) of diseases were also calculated in the whole population and subgroups. Abbreviations: PTV, protein truncating variant; HR, hazard ratio; CI, confidence intervalCC BY · PubMed Central

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Metadata

Authors
Yuan, H., Liu, Z., Chen, M., Xu, Q., Jiang, Y., Zhang, T., Suo, C., & Chen, X.
Affiliations
Fudan University (CN)
Corresponding author
  • Suo, Chen
  • Chen, Xingdong
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2024-06-11
Volume
22
Issue
1
Pages
239-239
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-024-03466-0
PMC
PMC11167739
OpenAlex
W4399544394
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (82122060, 82204125)
  • Fudan University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
truncating mutations, mitochondrial dysfunction, chronic liver disease, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, liver disease mortality, lipid metabolism, amino acid metabolism, carbohydrate metabolism, fatty acid metabolism, genetic risk
MeSH terms
Exome Sequencing, Adult, Aged, Chronic Disease, Female, United Kingdom, Humans, Liver Diseases, Male, Middle Aged, Genetic Variation, Genetic Predisposition to Disease, Genes, Mitochondrial

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