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Differential response to a 6-month energy-restricted treatment depending on SH2B1 rs7359397 variant in NAFLD subjects: Fatty Liver in Obesity (FLiO) Study

European Journal of Nutrition volume 60, pages 3043–3057 (2021)Cite this article

Abstract

Purpose

Non-alcoholic fatty liver disease (NAFLD) is worldwide recognized as the most common cause of chronic liver disease. Current NAFLD clinical management relies on lifestyle change, nevertheless, the importance of the genetic make-up on liver damage and the possible interactions with diet are still poorly understood. The aim of the study was to evaluate the influence of the SH2B1 rs7359397 genetic variant on changes in body composition, metabolic status and liver health after 6-month energy-restricted treatment in overweight/obese subjects with NAFLD. In addition, gene-treatment interactions over the course of the intervention were examined.

Methods

The SH2B1 genetic variant was genotyped in 86 overweight/obese subjects with NAFLD from the FLiO study (Fatty Liver in Obesity study). Subjects were metabolically evaluated at baseline and at 6-months. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, a lipidomic test (OWL®-test) and specific blood liver biomarkers. Additionally, body composition, general biochemical markers and dietary intake were determined.

Results

Both genotypes significantly improved their body composition, general metabolic status and liver health after following an energy-restricted strategy. Liver imaging techniques showed a greater decrease in liver fat content (− 44.3%, p < 0.001) and in serum ferritin levels (p < 0.001) in the carriers of the T allele after the intervention. Moreover, lipidomic analysis, revealed a higher improvement in liver status when comparing risk vs. no-risk genotype (p = 0.006 vs. p = 0.926, respectively). Gene-treatment interactions showed an increase in fiber intake and omega-3 fatty acid in risk genotype (p interaction = 0.056 and p interaction = 0.053, respectively), while a significant increase in MedDiet score was observed in both genotype groups (p = 0.020). Moreover, no-risk genotype presented a relevant decrease in hepatic iron as well as in MUFA intake (p = 0.047 and p = 0.034, respectively).

Conclusion

Subjects carrying the T allele of the rs7359397 polymorphism may benefit more in terms of hepatic health and liver status when prescribed an energy-restricted treatment, where a Mediterranean dietary pattern rich in fiber and other components such as omega-3 fatty acids might boost the benefits.

Trial registration

The Fatty Liver in Obesity was approved by the Research Ethics Committee of the University of Navarra and retrospectively registered (NCT03183193; www.clinicaltrials.gov); June 2017.

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Availability of data and material

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Abbreviations

AASLD:

American Association for the Study of Liver Diseases

AHA:

American Heart Association

AIP:

Atherogenic Index of Plasma

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body Mass Index

CRP:

C-reactive protein

DXA:

Dual-energy X-ray absorptiometry

EASL:

European Association for the Study of the Liver

FFQ:

Food Frequency Questionnaire

FLI:

Fatty Liver Index

FLiO:

Fatty liver in obesity

GGT:

Gamma-glutamyl transferase

GWAs:

Genome-wide associations

HCC:

Hepatocellular carcinoma

HDL-c:

High density lipoprotein cholesterol

HOMA-IR:

Homeostasis model assessment insulin resistance

IQR:

Interquartile ranges

LDL-c:

Low-density lipoprotein cholesterol

MedDiet Score:

Mediterranean Diet Score

METs:

Metabolic equivalent of the task

MRI:

Magnetic resonance imaging

MUFA:

Monounsaturated fatty acid

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

OWLiver® :

One Way Liver®

PA:

Physical activity

PUFA:

Polyunsaturated fatty acid

SD:

Standard deviations

SFA:

Saturated fatty acid

SH2 :

Src-homology-2

SH2B1 :

Src-homology-2 B adaptor protein 1

SNP:

Single nucleotide polymorphism

TC:

Total cholesterol

TG:

Triglycerides

TGs:

Triacylglycerols

TE:

Transient elastography

TyG index:

Triglycerides and Glucose Index

VAT:

Visceral adipose tissue

WC:

Waist circumference

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Acknowledgements

The authors are grateful to the volunteers of the study as well as Veronica Ciaurriz and to the nurses from the departments of Clinical Chemistry, Radiology, Internal Medicine and the Liver Unit of the Clinica Universidad de Navarra for their contribution to FLiO project. We also would like to thank Marta García Granero for statistical assistance. The pre-doctoral research grant to Nuria Pérez from the Centre for Nutrition Research of the University of Navarra is gratefully acknowledged. The tractor role from LABORATORIOS CINFA, S.A. and VISCOFAN S.A. for financial support of the Center for Nutrition Research as well as the support from the Government of Navarra are also appreciated. Finally, the authors wish to express their gratitude to the Government of Navarra, CIBERobn and Fundació La Marató de TV3 for the financial support.

Funding

This research was funded by the Health Department of the Government of Navarra (61/2015), CIBERobn (Physiopathology of Obesity and Nutrition) (CB12/03/3002) and Fundació La Marató de TV3 (201630.10).

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Author notes

  1. Itziar Abete and M. Angeles Zulet contributed equally to this work.

Authors and Affiliations

  1. Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain

    Nuria Perez-Diaz-del-Campo, Bertha Araceli Marin-Alejandre, Irene Cantero, Jose I. Riezu-Boj, Fermín I. Milagro, J. Alfredo Martinez, Itziar Abete & M. Angeles Zulet

  2. Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain

    Nuria Perez-Diaz-del-Campo, Bertha Araceli Marin-Alejandre, Irene Cantero, Jose I. Riezu-Boj, Fermín I. Milagro, J. Alfredo Martinez, Itziar Abete & M. Angeles Zulet

  3. Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain

    J. Ignacio Monreal, Mariana Elorz, José Ignacio Herrero, Alberto Benito-Boillos, Jose I. Riezu-Boj, Fermín I. Milagro, J. Alfredo Martinez, Itziar Abete & M. Angeles Zulet

  4. Clinical Chemistry Department, Clínica Universidad de Navarra, 31008, Pamplona, Spain

    J. Ignacio Monreal

  5. Department of Radiology, Clínica Universidad de Navarra, 31008, Pamplona, Spain

    Mariana Elorz & Alberto Benito-Boillos

  6. Liver Unit, Clínica Universidad de Navarra, 31008, Pamplona, Spain

    José Ignacio Herrero

  7. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain

    José Ignacio Herrero

  8. Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain

    Fermín I. Milagro, Josep A. Tur, J. Alfredo Martinez, Itziar Abete & M. Angeles Zulet

  9. Research Group on Community Nutrition and Oxidative Stress, University of Balearic Islands & Balearic Islands Institute for Health Research (IDISBA), 07122, Palma, Spain

    Josep A. Tur

Authors
  1. Nuria Perez-Diaz-del-Campo
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  2. Bertha Araceli Marin-Alejandre
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  3. Irene Cantero
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  4. J. Ignacio Monreal
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  5. Mariana Elorz
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  6. José Ignacio Herrero
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  7. Alberto Benito-Boillos
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  8. Jose I. Riezu-Boj
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  9. Fermín I. Milagro
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  10. Josep A. Tur
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  11. J. Alfredo Martinez
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  12. Itziar Abete
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  13. M. Angeles Zulet
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Contributions

NP-DC: conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, visualization, roles/writing—original draft; writing—review and editing. BAM-A: conceptualization, data curation, methodology. IC: conceptualization, methodology. JIM: conceptualization, methodology. ME: conceptualization, methodology. JIH: conceptualization, methodology. AB-B: conceptualization, methodology. JIR-B: conceptualization, methodology. FIM: conceptualization, methodology. JAT: conceptualization, formal analysis, funding acquisition, methodology. JAM: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, supervision, validation, visualization, roles/writing—original draft, writing—review and editing. IA: conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, roles/writing—original draft, writing—review and editing. MAZ: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, supervision, validation, visualization, roles/writing—original draft, writing—review and editing.

Corresponding authors

Correspondence to Itziar Abete or M. Angeles Zulet.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest concerning this research.

Ethical standards

The present study was approved by the Research Ethics Committee of the University of Navarra on 24 April 2015 (ref. 54/2015) and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its latter amendments.

Informed consent

All participants gave written informed consent in a clinical interview for their participation in the study.

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Perez-Diaz-del-Campo, N., Marin-Alejandre, B.A., Cantero, I. et al. Differential response to a 6-month energy-restricted treatment depending on SH2B1 rs7359397 variant in NAFLD subjects: Fatty Liver in Obesity (FLiO) Study. Eur J Nutr 60, 3043–3057 (2021). https://doi.org/10.1007/s00394-020-02476-x

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  • DOI: https://doi.org/10.1007/s00394-020-02476-x

Keywords

  • NAFLD
  • Gene-treatment interaction
  • SH2B1
  • Energy-restricted diet
  • Obesity
  • Weight-loss