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High red meat consumption among PNPLA3 polymorphism carriers is associated with NAFLD in a multi-center cross-sectional study

European Journal of Clinical Nutrition (2024)Cite this article

Subjects

Abstract

Background & Aim

Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphism has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD), with evidence for potential interaction with nutrition. However, the combination of meat consumption with genetic polymorphism has not been tested. Therefore, this study aims to test the association between the joint presence of PNPLA3 rs738409 G-allele with high meat consumption and NAFLD in populations with diverse meat consumption.

Methods

A cross-sectional study among Israeli screening and Brazilian primary healthcare populations. Food consumption was assessed by a food-frequency questionnaire. PNPLA3 polymorphism was defined as homozygous (GG) or heterozygous (GC). Inconclusive/probable NAFLD was defined as a fatty liver index (FLI) ≥ 30 and probable NAFLD as FLI ≥ 60.

Results

The sample included 511 subjects from the screening and primary healthcare populations (n = 213 and n = 298, respectively). Genetic polymorphism (homozygous GG or heterozygous GC) combined with high consumption of total meat, red and/or processed meat, unprocessed red meat, and processed meat was associated with the highest odds for inconclusive/probable NAFLD (OR = 2.75, 95%CI 1.27–5.97, p = 0.011; OR = 3.24, 1.43–7.34, p = 0.005; OR = 2.92, 1.32–6.47, p = 0.008; OR = 3.16, 1.46–6.83, p = 0.003, respectively), adjusting for age, gender, BMI, alcohol consumption, carbohydrate, and saturated fat intake. In addition, genetic polymorphism combined with high processed meat consumption was associated with the highest odds for probable NAFLD (OR = 2.40, 95%CI 1.04–5.56, p = 0.040).

Conclusions

High red meat intake may confer a greater risk for NAFLD among PNPLA3 polymorphism carriers. Prospective studies are needed to confirm these findings and consider minimizing red and processed meat consumption among PNPLA3 polymorphism carriers.

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Fig. 1: Flow chart of the populations by study center.
Fig. 2: Multivariable association between high1 processed meat consumption by PNPLA3 polymorphism2,3 and probable NAFLD (FLI ≥ 60), among the screening plus the primary care populations.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to ethical considerations, but are available from the corresponding author on reasonable request.

References

  1. Henry L, Paik J, Younossi ZM. Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world. Aliment Pharmacol Ther. 2022;56:942–56.

    Article  PubMed  CAS  Google Scholar 

  2. Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61.

    Article  PubMed  Google Scholar 

  3. Hassani Zadeh S, Mansoori A, Hosseinzadeh M. Relationship between dietary patterns and non‐alcoholic fatty liver disease: a systematic review and meta‐analysis. Journal of Gastroenterology and Hepatology. 2021;36:1470–8.

    Article  PubMed  Google Scholar 

  4. Kawaguchi T, Charlton M, Kawaguchi A, Yamamura S, Nakano D, Tsutsumi T, et al. Effects of Mediterranean diet in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials. Seminars in Liver Disease; 2021: Thieme Medical Publishers, Inc.; 2021. p. 225-34.

  5. Ivancovsky-Wajcman D, Fliss-Isakov N, Webb M, Bentov I, Shibolet O, Kariv R, et al. Ultra-processed food is associated with features of metabolic syndrome and non-alcoholic fatty liver disease. Liver Int 2021.

  6. He K, Li Y, Guo X, Zhong L, Tang S. Food groups and the likelihood of non-alcoholic fatty liver disease: a systematic review and meta-analysis. British Journal of Nutrition. 2020;124:1–13.

    Article  PubMed  CAS  Google Scholar 

  7. Zelber-Sagi S, Ivancovsky-Wajcman D, Fliss Isakov N, Webb M, Orenstein D, Shibolet O, et al. High red and processed meat consumption is associated with non-alcoholic fatty liver disease and insulin resistance. J Hepatol. 2018;68:1239–46.

    Article  PubMed  CAS  Google Scholar 

  8. Noureddin M, Zelber‐Sagi S, Wilkens LR, Porcel J, Boushey CJ, Le Marchand L, et al. Diet associations with nonalcoholic fatty liver disease in an ethnically diverse population: the Multiethnic Cohort. Hepatology. 2020;71:1940–52.

    Article  PubMed  CAS  Google Scholar 

  9. Soleimani D, Ranjbar G, Rezvani R, Goshayeshi L, Razmpour F, Nematy M. Dietary patterns in relation to hepatic fibrosis among patients with nonalcoholic fatty liver disease. Diabetes Metab Syndr Obes. 2019;12:315–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lahelma M, Luukkonen PK, Qadri S, Ahlholm N, Lallukka-Brück S, Porthan K, et al. Assessment of lifestyle factors helps to identify liver fibrosis due to non-alcoholic fatty liver disease in obesity. Nutrients. 2021;13:169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Hashemian M, Merat S, Poustchi H, Jafari E, Radmard A-R, Kamangar F, et al. Red meat consumption and risk of nonalcoholic fatty liver disease in a population with low meat consumption: the golestan cohort study. Am J Gastroenterol. 2021;116:1667–75.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim MN, Lo C-H, Corey KE, Luo X, Long L, Zhang X, et al. Red meat consumption, obesity, and the risk of nonalcoholic fatty liver disease among women: evidence from mediation analysis. Clin Nutr. 2022;41:356–64.

    Article  PubMed  CAS  Google Scholar 

  13. Ivancovsky-Wajcman D, Fliss-Isakov N, Grinshpan LS, Salomone F, Lazarus JV, Webb M, et al. High meat consumption is prospectively associated with the risk of non-alcoholic fatty liver disease and presumed significant fibrosis. Nutrients. 2022;14:3533.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017;58:247–55.

    Article  PubMed  CAS  Google Scholar 

  15. Wang X, Liu Z, Wang K, Wang Z, Sun X, Zhong L, et al. Additive effects of the risk alleles of PNPLA3 and TM6SF2 on non-alcoholic fatty liver disease (NAFLD) in a Chinese population. Front Genet. 2016;7:140.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sookoian S, Pirola CJ. Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53:1883–94.

    Article  PubMed  CAS  Google Scholar 

  18. Davis JN, Le KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr. 2010;92:1522–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One. 2012;7:e37827.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  20. Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Belt P, Liang T, et al. Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD. Am J Gastroenterol. 2021;116:994–1006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Souza Ade M, Pereira RA, Yokoo EM, Levy RB, Sichieri R. Most consumed foods in Brazil: National Dietary Survey 2008-2009. Rev Saude Publica. 2013;47:190S–199S.

    PubMed  Google Scholar 

  22. OECD-FAO Agricultural Outlook (Edition 2021) https://data.oecd.org/agroutput/meat-consumption.htm.

  23. Santana NMT, Mill JG, Velasquez-Melendez G, Moreira AD, Barreto SM, Viana MC, et al. Consumption of alcohol and blood pressure: Results of the ELSA-Brasil study. PLoS One. 2018;13:e0190239.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.

    Article  PubMed  Google Scholar 

  25. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.

  26. Wilett W. Nutritional epidemiology: New York: Oxford University Press; 1998.

  27. Cantwell M, Mittl B, Curtin J, Carroll R, Potischman N, Caporaso N, et al. Relative validity of a food frequency questionnaire with a meat-cooking and heterocyclic amine module. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive. Oncology. 2004;13:293–8.

    CAS  Google Scholar 

  28. Keinan-Boker L, Noyman N, Chinich A, Green MS, Nitzan-Kaluski D. Overweight and obesity prevalence in Israel: findings of the first national health and nutrition survey (MABAT). Isr Med Assoc J. 2005;7:219–23.

    PubMed  Google Scholar 

  29. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:1–7.

    Article  Google Scholar 

  30. Tabela brasileira de composição de alimentos: Núcleo de Estudos e Pesquisas em Alimentação. Universidade Estadual de Campinas; 2011.

  31. Dehmer GJ, Badhwar V, Bermudez EA, Cleveland JC Jr, Cohen MG, D’Agostino RS, et al. 2020 AHA/ACC key data elements and definitions for coronary revascularization: a report of the American College of Cardiology/American Heart Association task force on clinical data standards (writing committee to develop clinical data standards for coronary revascularization). J Am College Cardiol. 2020;75:1975–2088.

    Article  Google Scholar 

  32. Dai G, Liu P, Li X, Zhou X, He S. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) susceptibility and severity: A meta-analysis. Medicine (Baltimore). 2019;98:e14324.

    Article  PubMed  CAS  Google Scholar 

  33. Yoshimura SM, Duarte SMB, Stefano JT, Mazo DFC, Pinho JRR, Oliveira CP. Pnpla3 gene polymorphism and red meat consumption increased fibrosis risk in nash biopsy-proven patients under medical follow-up in a tertiary center in Southwest Brazil. Arq Gastroenterol. 2023;60:98–105.

    Article  PubMed  Google Scholar 

  34. Peng H, Xie X, Pan X, Zheng J, Zeng Y, Cai X, et al. Association of meat consumption with NAFLD risk and liver-related biochemical indexes in older Chinese: a cross-sectional study. BMC Gastroenterol. 2021;21:221.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ. 2017;357:j1957.

    Article  PubMed  PubMed Central  Google Scholar 

  36. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285:6706–15.

    Article  PubMed  CAS  Google Scholar 

  37. Bordoni L, Petracci I, Zhao F, Min W, Pierella E, Assmann TS, et al. Nutrigenomics of dietary lipids. Antioxidants (Basel). 2021;10:994.

    Article  PubMed  CAS  Google Scholar 

  38. Castellana M, Donghia R, Guerra V, Procino F, Lampignano L, Castellana F, et al. Performance of fatty liver index in identifying non-alcoholic fatty liver disease in population studies. A meta-analysis. J Clin Med. 2021;10:1877.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cuthbertson DJ, Weickert MO, Lythgoe D, Sprung VS, Dobson R, Shoajee-Moradie F, et al. External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals. Eur J Endocrinol. 2014;171:561–9.

    Article  PubMed  CAS  Google Scholar 

  40. Kim KS, Hong S, Han K, Park CY. Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study. BMJ. 2024;384:e076388.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chung GE, Jeong SM, Cho EJ, Yoon JW, Yoo JJ, Cho Y, et al. The association of fatty liver index and BARD score with all-cause and cause-specific mortality in patients with type 2 diabetes mellitus: a nationwide population-based study. Cardiovasc Diabetol. 2022;21:273.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Siafi E, Andrikou I, Thomopoulos C, Konstantinidis D, Kakouri N, Tatakis F, et al. Fatty liver index and cardiovascular outcomes in never-treated hypertensive patients: a prospective cohort. Hypertens Res. 2023;46:119–27.

    Article  PubMed  Google Scholar 

  43. Cuthbertson DJ, Koskinen J, Brown E, Magnussen CG, Hutri-Kahonen N, Sabin M, et al. Fatty liver index predicts incident risk of prediabetes, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Ann Med. 2021;53:1256–64.

    Article  PubMed  Google Scholar 

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Funding

This study was financed in part by: Research Grants and Fellowships Fund on Food and Nutrition and their Implications on Public Health, The Israeli Ministry of Health. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) -Finance Code 001. Conselho Nacional de DesenvolvimentoCientífico e Tecnológico, Brazil.

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Authors and Affiliations

  1. GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil

    Mario Reis Alvares-da-Silva, Soheyla Rabie, Larisse Longo, Carolina Uribe-Cruz & Dvora Joveleviths

  2. CNPq researcher, Brasília, Brazil

    Mario Reis Alvares-da-Silva & Claudia P. Oliveira

  3. School of Public Health, University of Haifa, 199 Aba Khoushy Ave., Haifa, 3498838, Israel

    Dana Ivancovsky-Wajcman, Laura Sol Grinshpan & Shira Zelber-Sagi

  4. Division of Clinical Gastroenterology and Hepatology (LIM-07), Hospital das Clinicas, Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo 455, 3115, Cerqueira Cesar, 01246-903, Sao Paulo, Brazil

    Claudia P. Oliveira & Silvia Massami Yoshimura

  5. Department of Gastroenterology Tel-Aviv Medical Center, 6 Weizman St., Tel-Aviv, 6423906, Israel

    Merav Ben-Yehoyada, Oren Shibolet, Revital Kariv & Shira Zelber-Sagi

  6. Sackler Faculty of Medicine, Tel-Aviv University, 30 Haim Lebanon St., Tel-Aviv, 6139601, Israel

    Oren Shibolet & Revital Kariv

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  1. Mario Reis Alvares-da-Silva
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Contributions

MRAS: study concept and design, analysis and interpretation of data, drafting of the manuscript; DIW: study concept and design, analysis and interpretation of data, statistical analysis; CPO: study concept and design, analysis and interpretation of data, drafting of the manuscript; SR: data collection; LL: data collection, analysis and interpretation of data, PNPLA3 polymorphism analysis; CUC: PNPLA3 polymorphism analysis; SMY: data collection; DJ: study concept and design; MBY: PNPLA3 polymorphism analysis; LSG: analysis and interpretation of data, critical revision of the manuscript for important intellectual content; OS: critical revision of the manuscript for important intellectual content; RR: study concept and design, critical revision of the manuscript for important intellectual content, study supervision; SZS: study concept and design, analysis and interpretation of data, drafting of the manuscript, study supervision.

Corresponding author

Correspondence to Shira Zelber-Sagi.

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The study was aproved by the IRB of each center.

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Alvares-da-Silva, M.R., Ivancovsky-Wajcman, D., Oliveira, C.P. et al. High red meat consumption among PNPLA3 polymorphism carriers is associated with NAFLD in a multi-center cross-sectional study. Eur J Clin Nutr (2024). https://doi.org/10.1038/s41430-024-01416-w

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