Skip to main content

Advertisement

SpringerLink
Log in

Diet-derived antioxidants and nonalcoholic fatty liver disease: a Mendelian randomization study

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background

Whether supplementation with diet-derived antioxidants is beneficial for nonalcoholic fatty liver disease (NAFLD) is still controversial and we hope to answer this question using population-based genetic data.

Methods

A total of 8485 NAFLD cases and 658,849 healthy controls from four independent NAFLD genome-wide association studies were enrolled in this study. Genetic variants closely associated with the diet-derived antioxidants were selected to predict their circulating levels. A bi-directional Mendelian randomization (MR) design was employed to assess their causations.

Results

Genetic correlation analyses suggested inverse associations between diet-derived antioxidants and NAFLD. MR analyses indicated that the odds ratio (OR) of per standard deviation increase in genetically predicted toenail and blood selenium was 1.179 for NAFLD (95% confidence interval [1.083–1.284]). Also, the genetically elevated selenium level was causally associated with increased levels of C-reactive protein, fibrinogen, alkaline phosphatase and glycated hemoglobin. The OR of 1 µg/dL increase in genetically predicted serum lycopene was 1.082 (95%CI [1.051–1.113]). No other causal associations were found for NAFLD. However, we observed protective effects of genetically predicted β-carotene (OR = 0.929[0.911–0.947]) and retinol (OR = 0.483[0.460–0.508]) on type 2 diabetes (T2D), and further they could reduce the serum levels of blood lipids and glucose. Reverse MR analysis suggested genetically predicated NAFLD status would not affect the levels of diet-derived antioxidants.

Conclusion

Overall, we observed the positive associations of genetically predicted selenium and lycopene with NAFLD. However, the genetically predicted β-carotene and retinol levels were inversely associated with the risk of T2D.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data materials

All genome-wide association studies can be accessed via GWAS Catalog database (https://www.ebi.ac.uk/gwas/) and Open GWAS database (https://gwas.mrcieu.ac.uk/). The summary statistics of GWAS meta-analyses generated in this study can be accessible upon request.

Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

MAFLD:

Metabolic dysfunction-associated fatty liver disease

MR:

Mendelian randomization

SNP:

Single nucleotide polymorphism

GWAS:

Genome-wide association study

CRP:

C-reactive protein

ALT:

Alanine aminotransferase

AST:

Aspartate transferase

ALP:

Alkaline phosphatase

γ-GT:

γ-Glutamyl transferase

T2D:

Type 2 diabetes

LDSC:

Linkage disequilibrium score regression

LD:

Linkage disequilibrium

BMI:

Body mass index

WHR:

Waist-to-hip ratio

UKB:

UK biobank

OR:

Odds ratio

HbA1c:

Glycated hemoglobulin

LDL:

Low-density lipoprotein

TC:

Total cholesterol

HDL:

High-density lipoprotein

TG:

Triglycerides

FI:

Fasting insulin

STROBE-MR:

Strengthening the reporting of observational studies in epidemiology-Mendelian randomization

eMERGE:

Electronic medical records and genomics

GOLD:

Genetics of obesity-related liver disease

IVW:

Inverse variance weighted

FDR:

False discovery rate

MRPRESSO:

Mendelian randomization pleiotropy residual sum and outlier

IVs:

Instrumental variables

NHANES:

National health and nutrition examination survey

References

  1. Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158:1999-2014.e1991

    Article  CAS  PubMed  Google Scholar 

  2. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547–1558

    Article  CAS  PubMed  Google Scholar 

  4. He Z, Li X, Yang H, Wu P, Wang S, Cao D, et al. Effects of oral vitamin C supplementation on liver health and associated parameters in patients with non-alcoholic fatty liver disease: a randomized clinical trial. Front Nutr. 2021;8: 745609

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sugiura M, Nakamura M, Ogawa K, Ikoma Y, Yano M. High serum carotenoids are associated with lower risk for developing elevated serum alanine aminotransferase among Japanese subjects: the Mikkabi cohort study. Br J Nutr. 2016;115:1462–1469

    Article  CAS  PubMed  Google Scholar 

  6. Ma C, Liu Y, He S, Zeng J, Li P, Ma C, et al. Negative association between antioxidant vitamin intake and non-alcoholic fatty liver disease in Chinese non-diabetic adults: mediation models involving superoxide dismutase. Free Radic Res. 2020;54:670–677

    Article  CAS  PubMed  Google Scholar 

  7. Xiao ML, Zhong HL, Lin HR, Liu CY, Yan Y, Ke YB, et al. Higher serum vitamin A is associated with a worsened progression of non-alcoholic fatty liver disease in adults: a prospective study. Food Funct. 2022;13:970–977

    Article  CAS  PubMed  Google Scholar 

  8. Jeon D, Son M, Shim J. Dynamics of serum retinol and alpha-tocopherol levels according to non-alcoholic fatty liver disease status. Nutrients. 2021;13:1720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Davies NM, Holmes MV, Davey SG. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362: k601

    Article  PubMed  PubMed Central  Google Scholar 

  10. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Luo J, le Cessie S, van Heemst D, Noordam R. Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study. J Am Coll Cardiol. 2021;77:45–54

    Article  CAS  PubMed  Google Scholar 

  12. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Patterson N, et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, et al. A global reference for human genetic variation. Nature. 2015;526:68–74

    Article  PubMed  Google Scholar 

  16. Skrivankova VW, Richmond RC, Woolf BAR, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375: n2233

    Article  PubMed  PubMed Central  Google Scholar 

  17. Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA. 2021;326:1614–1621

    Article  PubMed  Google Scholar 

  18. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7: e1001324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–389

    Article  PubMed  PubMed Central  Google Scholar 

  20. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang X, Seo YA, Park SK. Serum selenium and non-alcoholic fatty liver disease (NAFLD) in U.S. adults: national health and nutrition examination survey (NHANES) 2011–2016. Environ Res. 2021;197:111190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang Z, Yan C, Liu G, Niu Y, Zhang W, Lu S, et al. Plasma selenium levels and nonalcoholic fatty liver disease in Chinese adults: a cross-sectional analysis. Sci Rep. 2016;6:37288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu J, Zeng C, Yang Z, Li X, Lei G, Xie D, et al. Association between dietary selenium intake and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study. J Am Coll Nutr. 2020;39:103–111

    Article  PubMed  Google Scholar 

  24. Urbano T, Filippini T, Lasagni D, De Luca T, Grill P, Sucato S, et al. Association of urinary and dietary selenium and of serum selenium species with serum alanine aminotransferase in a healthy Italian population. Antioxidants (Basel). 2021;10:1516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Park K, Rimm EB, Siscovick DS, Spiegelman D, Manson JE, Morris JS, et al. Toenail selenium and incidence of type 2 diabetes in U.S. male and female. Diabetes Care. 2012;35:1544–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lazard M, Dauplais M, Blanquet S, Plateau P. Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells. Biomol Concepts. 2017;8:93–104

    Article  CAS  PubMed  Google Scholar 

  27. Li J, Yu J, Yang J, Cui J, Sun Y. Dietary iron and zinc intakes and nonalcoholic fatty liver disease: a meta-analysis. Asia Pac J Clin Nutr. 2021;30:704–714

    CAS  PubMed  Google Scholar 

  28. Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol. 2006;20:3–18

    Article  CAS  PubMed  Google Scholar 

  29. Song X, Luo Y, Ma L, Hu X, Simal-Gandara J, Wang LS, et al. Recent trends and advances in the epidemiology, synergism, and delivery system of lycopene as an anti-cancer agent. Semin Cancer Biol. 2021;73:331–346

    Article  CAS  PubMed  Google Scholar 

  30. Xiao ML, Chen GD, Zeng FF, Qiu R, Shi WQ, Lin JS, et al. Higher serum carotenoids associated with improvement of non-alcoholic fatty liver disease in adults: a prospective study. Eur J Nutr. 2019;58:721–730

    Article  CAS  PubMed  Google Scholar 

  31. Iqbal WA, Mendes I, Finney K, Oxley A, Lietz G. Reduced plasma carotenoids in individuals suffering from metabolic diseases with disturbances in lipid metabolism: a systematic review and meta-analysis of observational studies. Int J Food Sci Nutr. 2021;72:879–891

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Zhao Y, Liu K, Li Z, Tan X, Wang Y, et al. Lycopene aggravates acute gastric injury induced by ethanol. Front Nutr. 2021;8: 697879

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wei J, Lei GH, Fu L, Zeng C, Yang T, Peng SF. Association between dietary vitamin c intake and non-alcoholic fatty liver disease: a cross-sectional study among middle-aged and older adults. PLoS One. 2016;11: e0147985

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zheng JS, Luan J, Sofianopoulou E, Imamura F, Stewart ID, Day FR, et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care. 2021;44:98–106

    Article  CAS  PubMed  Google Scholar 

  35. Lawlor DA, Davey Smith G, Kundu D, Bruckdorfer KR, Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet. 2004;363:1724–1727

    Article  PubMed  Google Scholar 

  36. Lee SW, Baek SM, Kang KK, Lee AR, Kim TU, Choi SK, et al. Vitamin C deficiency inhibits nonalcoholic fatty liver disease progression through impaired de novo lipogenesis. Am J Pathol. 2021;191:1550–1563

    Article  CAS  PubMed  Google Scholar 

  37. Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2019;42:1481–1488

    Article  CAS  PubMed  Google Scholar 

  38. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wallström P, Wirfält E, Lahmann PH, Gullberg B, Janzon L, Berglund G. Serum concentrations of beta-carotene and alpha-tocopherol are associated with diet, smoking, and general and central adiposity. Am J Clin Nutr. 2001;73:777–785

    Article  PubMed  Google Scholar 

  40. Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol. 2020;73:263–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun YQ, Burgess S, Staley JR, Wood AM, Bell S, Kaptoge SK, et al. Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear Mendelian randomisation analyses. BMJ. 2019;364: l1042

    Article  PubMed  PubMed Central  Google Scholar 

  42. Morrison J, Knoblauch N, Marcus JH, Stephens M, He X. Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet. 2020;52:740–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We want to acknowledge the participants and investigators of the FinnGen study. We want to thank MRC-IEU and Neale Lab for making UK Biobank GWAS summary statistics openly available. Besides, we would like to thank all the other investigators for making summary statistics openly available.

Funding

The work is supported by the Financial Department of Jilin Province (Grant NO. JLSWSRCZX2021-026; Grant NO. JLSWSRCZX2020-045; Grant NO. 2018SCZWSZX-033).

Author information

Author notes

  1. Lanlan Chen and Zhongqi Fan have contributed equally to this study.

Authors and Affiliations

  1. Hepatobiliary and Pancreatic Surgery Department, General Surgery Center, First Hospital of Jilin University, No.1 Xinmin Street, Changchun, 130021, Jilin, China

    Lanlan Chen, Zhongqi Fan, Xiaodong Sun, Wei Qiu, Wentao Mu, Kaiyuan Chai, Yannan Cao, Guangyi Wang & Guoyue Lv

Authors
  1. Lanlan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongqi Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaodong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wentao Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kaiyuan Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yannan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guangyi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guoyue Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GL and LC proposed and designed the research. LC undertook data collection and performed the main data analysis. ZF checked the statistical analysis. LC and ZF wrote the draft of the manuscript. XS and WQ were responsible for reviewing and substantially revising the manuscript. WM visualized the results and revised the manuscript. KC and YC were responsible for reviewing the statistical methods. GW provided necessary advice and revised the manuscript. GL supervised the whole research and claimed the integrity of data analysis.

Corresponding author

Correspondence to Guoyue Lv.

Ethics declarations

Conflict of interest

Lanlan Chen, Zhongqi Fan, Xiaodong Sun, Wei Qiu, Wentao Mu, Kaiyuan Chai, Yannan Cao, Guangyi Wang and Guoyue Lv  declare that they have no conflicts of interest.

Ethics approval and consent to participate

Each genome-wide association study (GWAS) has been approved by its corresponding Ethical Review Committee. This study was exempted from the Ethical Review Committee of the First Hospital of Jilin University since all GWAS summary statistics are openly available and can be used and analyzed without restriction except for identifying the individual-level information.

Consent for publication

Each author has given his/her consent to publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 10691 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, L., Fan, Z., Sun, X. et al. Diet-derived antioxidants and nonalcoholic fatty liver disease: a Mendelian randomization study. Hepatol Int 17, 326–338 (2023). https://doi.org/10.1007/s12072-022-10443-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-022-10443-3

Keywords

Search

Navigation