CoChat
Sign Up
Cited by 3Genetic Associations and EpidemiologyMitochondrial Function and PathologyGenomics and Rare Diseases

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

Open access
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
Open this paper in CoChat — free account

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12916-024-03466-0

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Figures

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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 1 references

Research works printed but not linked: 30

  1. Sepanlou SG, Safiri S, Bisignano C, Ikuta KS, Merat S, Saberifiroozi M, Poustchi H, Tsoi D, Colombara DV, Abdoli A, et al. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245–66. · DOI · Paper page
  2. Cheemerla S, Balakrishnan M. Global epidemiology of chronic liver disease. Clin Liver Dis (Hoboken). 2021;17(5):365–70. · DOI · Paper page
  3. Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022;34(7):969-977.e962. · DOI
  4. Morio B, Panthu B, Bassot A, Rieusset J. Role of mitochondria in liver metabolic health and diseases. Cell Calcium. 2021;94:102336. · DOI
  5. El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta Mol Basis Dis. 2017;1863(6):1539–55. · DOI
  6. Ramanathan R, Ali AH, Ibdah JA. Mitochondrial dysfunction plays central role in nonalcoholic fatty liver disease. Int J Mol Sci. 2022;23(13):7280. · DOI
  7. Lee HY, Nga HT, Tian J, Yi HS. Mitochondrial metabolic signatures in hepatocellular carcinoma. Cells. 2021;10(8):1901. · DOI
  8. Kraja AT, Liu C, Fetterman JL, Graff M, Have CT, Gu C, Yanek LR, Feitosa MF, Arking DE, Chasman DI, et al. Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits. Am J Hum Genet. 2019;104(1):112–38. · DOI
  9. DeBoever C, Tanigawa Y, Lindholm ME, McInnes G, Lavertu A, Ingelsson E, Chang C, Ashley EA, Bustamante CD, Daly MJ, et al. Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study. Nat Commun. 2018;9(1):1612. · DOI
  10. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–9. · DOI · Paper page
  11. Backman JD, Li AH, Marcketta A, Sun D, Mbatchou J, Kessler MD, Benner C, Liu D, Locke AE, Balasubramanian S, et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature. 2021;599(7886):628–34. · DOI
  12. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F. The Ensembl Variant Effect Predictor. Genome Biol. 2016;17(1):122. · DOI · Paper page
  13. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. · DOI · Paper page
  14. Rath S, Sharma R, Gupta R, Ast T, Chan C, Durham TJ, Goodman RP, Grabarek Z, Haas ME, Hung WHW, et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021;49(D1):D1541-d1547. · DOI · Paper page
  15. Smith AC, Robinson AJ. MitoMiner v4.0: an updated database of mitochondrial localization evidence, phenotypes and diseases. Nucleic Acids Res. 2019;47(D1):D1225-d1228. · DOI
  16. Cotter D, Guda P, Fahy E, Subramaniam S. MitoProteome: mitochondrial protein sequence database and annotation system. Nucleic Acids Res. 2004;32(Database issue):D463-467. · DOI
  17. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. · DOI · Paper page
  18. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7. · DOI · Paper page
  19. Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep. 2018;20(2):12. · DOI · Paper page
  20. Schwantes-An TH, Darlay R, Mathurin P, Masson S, Liangpunsakul S, Mueller S, Aithal GP, Eyer F, Gleeson D, Thompson A, et al. Genome-wide association study and meta-analysis on alcohol-associated liver cirrhosis identifies genetic risk factors. Hepatology. 2021;73(5):1920–31. · DOI
  21. Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Gustot T, Deviere J, Debette S, et al. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int J Cancer. 2019;144(3):533–44. · DOI
  22. Emdin CA, Haas M, Ajmera V, Simon TG, Homburger J, Neben C, Jiang L, Wei WQ, Feng Q, Zhou A, et al. Association of genetic variation with cirrhosis: a multi-trait genome-wide association and gene-environment interaction study. Gastroenterology. 2021;160(5):1620-1633.e1613. · DOI
  23. Bendapudi PK, Nazeen S, Ryu J, Söylemez O, Robbins A, Rouaisnel B, O’Neil JK, Pokhriyal R, Yang M, Colling M, et al. Low-frequency inherited complement receptor variants are associated with purpura fulminans. Blood. 2024;143(11):1032–44. · DOI
  24. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43(11):1131–8. · DOI
  25. Chen VL, Du X, Chen Y, Kuppa A, Handelman SK, Vohnoutka RB, Peyser PA, Palmer ND, Bielak LF, Halligan B, et al. Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology. Nat Commun. 2021;12(1):816. · DOI
  26. Liu Z, Suo C, Jiang Y, Zhao R, Zhang T, Jin L, Chen X. Phenome-wide association analysis reveals novel links between genetically determined levels of liver enzymes and disease phenotypes. Phenomics. 2022;2(5):295–311. · DOI
  27. Ozaki M. Cellular and molecular mechanisms of liver regeneration: proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol. 2020;100:62–73. · DOI
  28. Yan S, Yang XF, Liu HL, Fu N, Ouyang Y, Qing K. Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. World J Gastroenterol. 2015;21(12):3492–8. · DOI
  29. Mansouri A, Gattolliat CH, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology. 2018;155(3):629–47. · DOI
  30. Ortiz M, Soto-Alarcón SA, Orellana P, Espinosa A, Campos C, López-Arana S, Rincón MA, Illesca P, Valenzuela R, Videla LA. Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration. Dig Liver Dis. 2020;52(8):895–904. · DOI

Cited by

Sorted by citations

See all 3

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease. https://app.cochat.ai/papers/10.1186/s12916-024-03466-0
The paper
Yuan, H., Liu, Z., Chen, M., Xu, Q., Jiang, Y., Zhang, T., Suo, C., & Chen, X. (2024). Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease. BMC Medicine. https://doi.org/10.1186/s12916-024-03466-0