PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsy-proven Nonalcoholic Fatty Liver Disease

Gang Li; Liang-Jie Tang; Pei-Wu Zhu; Ou-Yang Huang; Rafael S Rios; Kenneth I Zheng; Sui-Dan Chen; Hong-Lei Ma; Giovanni Targher; Christopher D Byrne; Xiao-Yan Pan; Ming-Hua Zheng

doi:10.14218/JCTH.2021.00286

PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsy-proven Nonalcoholic Fatty Liver Disease

J Clin Transl Hepatol. 2022 Jun 28;10(3):439-448. doi: 10.14218/JCTH.2021.00286. Epub 2021 Oct 22.

Authors

Gang Li¹, Liang-Jie Tang¹, Pei-Wu Zhu², Ou-Yang Huang¹, Rafael S Rios¹, Kenneth I Zheng¹, Sui-Dan Chen³, Hong-Lei Ma¹, Giovanni Targher⁴, Christopher D Byrne⁵, Xiao-Yan Pan⁶, Ming-Hua Zheng^{1

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Affiliations

¹ NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
² Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
³ Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁴ Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
⁵ Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK.
⁶ Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁷ Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁸ Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China.

Abstract

Background and aims: Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease (NAFLD). We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.

Methods: The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD. Visceral fat area (VFA) was measured by bioelectrical impedance. Significant liver fibrosis (SF), defined as stage F ≥2 on histology, was the outcome measure of interest.

Results: The distribution of PNPLA3 genotypes was CC: 27.5%, CG: 48.2%, and GG: 24.3%. Higher VFA was associated with greater risk of having SF (adjusted-odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02-1.04, p<0.05), independent of potential confounders. Among subjects with the same VFA level, the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not. Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF. VFA remained significantly associated with SF only among the rs738409 G-allele carriers (adjusted-OR: 1.05; 95% CI: 1.03-1.08 for the GG group; and adjusted-OR:1.03; 95% CI: 1.01-1.04 for the GC group). There was a significant interaction between VFA and PNPLA3 rs738409 genotype (P _interaction =0.004).

Conclusions: PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD. Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF.

Keywords: Metabolic dysfunction-associated fatty liver disease; Nonalcoholic fatty liver disease; Significant fibrosis; Single nucleotide polymorphism; Visceral fat area.