Association of NAFLD with FGF21 Polygenic Hazard Score, and Its Interaction with Protein Intake Level in Korean Adults

Hae Jin Lee, Jinyoung Shon, Yoon Jung Park

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Fibroblast growth factor 21 (FGF21) is a hormone that participates in the regulation of energy homeostasis and is induced by dietary protein restriction. Preclinical studies have suggested that FGF21 induction exerts a protective effect against non-alcoholic fatty liver disease (NAFLD), while human studies have revealed elevated levels of and potential resistance to FGF21 in patients with NAFLD. However, whether the FGF21 pathway also contributes to NAFLD risk at the genetic level remains uncertain. A few attempts to investigate the impact of individual genetic variants at the loci encoding FGF21 and its receptors on NAFLD risk have failed to establish a clear association due to a limited effect size. Therefore, this study aimed to (1) develop a polygenic hazard score (PHS) for FGF21-related loci that are associated with NAFLD risk and (2) investigate the effect of its interaction with protein intake level on NAFLD risk. Data on 3501 participants of the Korean Genome Epidemiology Study (Ansan–Ansung) were analyzed. Eight single-nucleotide polymorphisms of fibroblast growth factor receptors and beta-klotho were selected for PHS determination using forward stepwise analysis. The association between the PHS and NAFLD was validated (p-trend: 0.0171 for men and <0.0001 for women). Moreover, the association was significantly modulated by the protein intake level in all participants as well as women (p-interaction = 0.0189 and 0.0131, respectively) but not in men. In particular, the women with the lowest PHS values and a protein intake lower than the recommended nutrient intake (RNI) exhibited a greater NAFLD risk (HR = 2.021, p-trend = 0.0016) than those with an intake equal to or greater than the RNI; however, those with higher PHS values had a high risk, regardless of protein intake level. These findings demonstrate the contribution of FGF21-related genetic variants and restricted protein intake to NAFLD incidence.

Original languageEnglish
Article number2385
Issue number10
StatePublished - May 2023

Bibliographical note

Funding Information:
This study was supported by Basic Science Research Programs through the National Research Foundation (NRF) funded by the Korean government (2021R1A2C2012578).

Funding Information:
This study was conducted with bioresources from National Biobank of Korea, the Korea Disease Control and Prevention Agency, Republic of Korea (KBN-2021-035). H.J.L and J.S. were supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Republic of Korea) and the National Research Foundation of Korea (NRF-5199990614253, Education Research Center for 4IR-Based Health Care).

Publisher Copyright:
© 2023 by the authors.


  • fibroblast growth factor 21 (FGF21)
  • non-alcoholic fatty liver disease (NAFLD)
  • polygenic hazard scores (PHS)
  • protein intake
  • recommended nutrient intake (RNI)


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