Skip to main content
SpringerLink
Log in

No association of NAFLD-related polymorphisms in PNPLA3 and TM6SF2 with all-cause and cardiovascular mortality in an Austrian population study

  • original article
  • Published:
Wiener klinische Wochenschrift Aims and scope Submit manuscript

Summary

Background and aims

Single-nucleotide-polymorphisms in PNPLA3-rs738409 and the TM6SF2-rs58542926, associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), have been discussed as potentially protective for cardiovascular diseases. Therefore, we aimed to study the associations of PNPLA3/TM6SF2 variants with MAFLD and cardiovascular risk in a population-based sample of asymptomatic patients.

Methods

The study cohort comprised 1742 patients of European decent aged 45–80 years from a registry study undergoing screening colonoscopy for colorectal cancer between 2010 and 2014. SCORE2 and Framingham risk score calculated to assess cardiovascular risk. Data on survival were obtained from the national death registry

Results

Half of included patients were male (52%, 59 ± 10 years), 819 (47%) carried PNPLA3‑G and 278 (16%) TM6SF2-T-alleles. MAFLD (PNPLA3‑G-allele: 46% vs. 41%, p = 0.041; TM6SF2‑T-allele: 54% vs. 42%, p < 0.001) was more frequent in patients harbouring risk alleles with both showing independent associations with MAFLD on multivariable binary logistic regression analysis. While median Framingham risk score was lower in PNPLA3‑G-allele carriers (10 vs. 8, p = 0.011), SCORE2 and established cardiovascular diseases were similar across carriers vs. non-carriers of the respective risk-alleles. During a median follow-up of 9.1 years, neither PNPLA3‑G-allele nor TM6SF2‑T-allele was associated with overall nor with cardiovascular mortality.

Conclusion

Carriage of PNPLA3/TM6SF2 risk alleles could not be identified as significant factor for all-cause or cardiovascular mortality in asymptomatic middle-aged individuals undergoing screening colonoscopy.

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

Similar content being viewed by others

Abbreviations

95%CI:

95% confidence interval

BMI:

body mass index

CVD:

cardiovascular disease

GWAS:

genome-wide association studies

HDL‑C:

high-density lipoprotein cholesterol

HOMA-IR:

Homeostatic Model Assessment for Insulin Resistance

IQR:

interquartile range

LDL:

low-density lipoprotein

MAFLD:

metabolic (dysfunction) associated fatty liver disease

NAFLD:

non-alcoholic fatty liver disease

PNPLA3:

patatin-like phospholipase domain-containing protein 3

SD:

standard deviation

SNP:

single nucleotide polymorphisms

TM6SF2:

transmembrane 6 superfamily 2

References

  1. Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab. 2021;50:101111.

    Article  CAS  PubMed  Google Scholar 

  2. Speliotes EK, 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(3):e1001324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Balcar L, et al. PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center. Dig Liver Dis. 2022;54(1):84–90.

    Article  PubMed  Google Scholar 

  4. Unalp-Arida A, Ruhl CE. Patatin-like phospholipase domain-containing protein 3 I148M and liver fat and fibrosis scores predict liver disease mortality in the U.S. population. Hepatology. 2020;71(3):820–34.

    Article  CAS  PubMed  Google Scholar 

  5. Abul-Husn NS, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu YL, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309.

    Article  CAS  PubMed  Google Scholar 

  7. Mancina RM, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5):1219–1230e6.

    Article  CAS  PubMed  Google Scholar 

  8. Strnad P, et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut. 2019;68(6):1099–107.

    Article  CAS  PubMed  Google Scholar 

  9. Holmen OL, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014;46(4):345–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kahali B, et al. TM6SF2: catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease? Gastroenterology. 2015;148(4):679–84.

    Article  PubMed  Google Scholar 

  11. Dongiovanni P, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61(2):506–14.

    Article  CAS  PubMed  Google Scholar 

  12. Liu DJ, et al. Exome-wide association study of plasma lipids in 〉300,000 individuals. Nat Genet. 2017;49(12):1758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Simons N, et al. PNPLA3, TM6SF2, and MBOAT7 genotypes and coronary artery disease. Gastroenterology. 2017;152(4):912–3.

    Article  CAS  PubMed  Google Scholar 

  14. Wernly S, et al. A sex-specific propensity-adjusted analysis of colonic adenoma detection rates in a screening cohort. Sci Rep. 2021;11(1):17785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Semmler G, et al. Nut consumption and the prevalence and severity of non-alcoholic fatty liver disease. PLoS ONE. 2020;15(12):e244514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Eslam M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.03.039.

    Article  PubMed  Google Scholar 

  17. Wilson PW, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–47.

    Article  CAS  PubMed  Google Scholar 

  18. group, S.w., E.C.r. collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439–54.

    Article  Google Scholar 

  19. Kedenko L, et al. Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort. BMC Med Genet. 2014;15:112.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169(4):505–14.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Krawczyk M, Liebe R, Lammert F. Toward genetic prediction of nonalcoholic fatty liver disease trajectories: PNPLA3 and beyond. Gastroenterology. 2020;158(7):1865–1880.e1.

    Article  CAS  PubMed  Google Scholar 

  22. Rüschenbaum S, et al. Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events. Hepatol Commun. 2018;2(7):798–806.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wijarnpreecha K, et al. PNPLA3 gene polymorphism and overall and cardiovascular mortality in the United States. J Gastroenterol Hepatol. 2020;35(10):1789–94.

    Article  CAS  PubMed  Google Scholar 

  24. BasuRay S, et al. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci USA. 2019;116(19):9521–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scorletti E, Carr RM. A new perspective on NAFLD: focusing on lipid droplets. J Hepatol. 2022;76(4):934–45.

    Article  CAS  PubMed  Google Scholar 

  26. Luo F, Oldoni F, Das A. TM6SF2: a novel genetic player in nonalcoholic fatty liver and cardiovascular disease. Hepatol Commun. 2022;6(3):448–60.

    Article  CAS  PubMed  Google Scholar 

  27. Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: A meta-analysis. Hepatology. 2015;62(6):1742–56.

    Article  CAS  PubMed  Google Scholar 

  28. Stojkovic IA, et al. The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels. Genes Nutr. 2014;9(2):388–388.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Krarup NT, et al. The PNPLA3 rs738409 G‑allele associates with reduced fasting serum triglyceride and serum cholesterol in danes with impaired glucose regulation. PLoS ONE. 2012;7(7):e40376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Krawczyk M, et al. The common adiponutrin variant p.I148M does not confer gallstone risk but affects fasting glucose and triglyceride levels. J Physiol Pharmacol. 2011;62(3):369–75.

    CAS  PubMed  Google Scholar 

  31. Kantartzis K, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes. 2009;58(11):2616–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Valenti L, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–17.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria

    Georg Semmler, Lorenz Balcar, Sarah Wernly, Leonora Datz, Marie Semmler, Bernhard Wernly & Christian Datz M.D.

  2. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Georg Semmler & Lorenz Balcar

  3. First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria

    Lea Rosenstatter & Elmar Aigner

  4. Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland

    Felix Stickel

  5. Institute of General Practice, Family Medicine and Preventive Medicine, Paracelsus Medical University, Salzburg, Austria

    Bernhard Wernly

Authors
  1. Georg Semmler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lorenz Balcar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah Wernly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonora Datz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Semmler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lea Rosenstatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Felix Stickel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elmar Aigner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernhard Wernly
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christian Datz M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design (G.S., L.B., C.D.), acquisition of data (all authors), analysis and interpretation of data (G.S., L.B., C.D.), drafting of the manuscript (G.S., L.B., C.D.), critical revision of the manuscript for important intellectual content (all authors).

Corresponding author

Correspondence to Christian Datz M.D..

Ethics declarations

Conflict of interest

G. Semmler, L. Balcar, S. Wernly, L. Datz, M. Semmler, L. Rosenstatter, F. Stickel, E. Aigner, B. Wernly and C. Datz declare that they have no competing interests.

Ethical standards

All patients provided written informed consent, and the study was approved by the local ethics committee (approval no. 415-E/1262/2-2010).

Additional information

Publisher’s Note

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

Authors Georg Semmler and Lorenz Balcar share co-first authorship.

Data sharing Statement:

Data are available from the corresponding author upon reasonable request.

Supplementary Information

508_2023_2196_MOESM1_ESM.docx

Supplementary data including Supplementary methods for the definition of the metabolic syndrome, and supplementary results including data on reasons for death, comparison of patient characteristics between PNPLA3 C/C vs. G/C vs. G/G, the patient flow-chart, and Kaplan-Meier curves cardiovascular mortality

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Semmler, G., Balcar, L., Wernly, S. et al. No association of NAFLD-related polymorphisms in PNPLA3 and TM6SF2 with all-cause and cardiovascular mortality in an Austrian population study. Wien Klin Wochenschr (2023). https://doi.org/10.1007/s00508-023-02196-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00508-023-02196-2

Keywords

Search

Navigation