Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals

Zewen Sun; Xingchen Pan; Aowen Tian; Ida Surakka; Tao Wang; Xu Jiao; Shanshan He; Jinfang Song; Xin Tian; Dan Tong; Jianping Wen; Yonggang Zhang; Wanqing Liu; Peng Chen

doi:10.1016/j.jhepr.2023.100744

Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals

JHEP Rep. 2023 Mar 27;5(7):100744. doi: 10.1016/j.jhepr.2023.100744. eCollection 2023 Jul.

Authors

Zewen Sun¹, Xingchen Pan², Aowen Tian^{3

4}, Ida Surakka^{5

6

7}, Tao Wang⁸, Xu Jiao⁸, Shanshan He⁸, Jinfang Song⁹, Xin Tian⁹, Dan Tong¹⁰, Jianping Wen¹, Yonggang Zhang^{11

12}, Wanqing Liu^{13

14}, Peng Chen^{1

3

4}

Affiliations

¹ Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
² Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China.
³ Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, China.
⁴ Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
⁵ Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁸ Software College of Jilin University, Changchun, China.
⁹ Department of Pediatrics, The Second Hospital of Jilin University, Changchun, China.
¹⁰ Department of Radiology, The First Hospital of Jilin University, Changchun, China.
¹¹ The Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China.
¹² College of Computer Science and Technology, Jilin University, Changchun, China.
¹³ Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
¹⁴ Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.

Abstract

Background & aims: Around 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD.

Methods: NAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD.

Results: Lean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, HFE rs1800562, SLC17A3-SLC17A2-TRIM38 rs9348697, PNPLA3 rs738409, and TM6SF2 rs58542926, were associated with lean NAFLD (p <5 × 10^-8). HFE rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis.

Conclusions: Our study suggested that HFE plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis.

Impact and implications: Lean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD.

Keywords: BMI; Genome-wide association study; Hepatic iron; Magnetic resonance imaging; Non-alcoholic fatty liver disease.