PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression.

Methods: We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists.

Results: The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers.

Conclusion: The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.

Keywords: MASLD; PNPLA3; gene–environment interaction; liver disease progression; personalised therapy.

FIGURE 1

What is gene environment interaction and how does it work for PNPLA3 I148M? This figure illustrates the synergistic effects of genetic and environmental factors (Alcohol [79], high‐caloric diet [33], diabetes [53] and obesity [15]) on the development of steatotc liver disease in individuals carrying the PNPLA3 I148M variant. SLD, steatotic liver disease. Created in BioRender. Schneider, C. (2022) BioRender.com/x46p701.

FIGURE 2

Overview of PNPLA3 I148M interaction. Schematic representation of the interactions between PNPLA3 I148M and various factors influencing the development of steatotic liver disease as well as progression from steatotic liver disease to steatohepatitis and cirrhosis. The central pathway highlights the role of PNPLA3 in liver disease progression. Modifying factors include diet (carbohydrates, vegetables, sweet drinks, manganese and fibre), obesity, drugs (omega‐3, statins), exercise (steps per day), social factors (alcohol, social status), genetics (LEPR, GCKR, AGTR1, TM6SF2) and sex. These factors contribute to the risk and progression of liver disease in individuals with the PNPLA3 variant. AGTR1, angiotensin II receptor Type 1; GCKR, gGlucokinase regulatory protein; LEPR, leptin receptor; MASH, metabolic dysfunction‐associated steatohepatitis; MASLD, metabolic dysfunction‐associated steatotic liver disease; TM6SF2, transmembrane 6 superfamily member 2. Created in BioRender. Schneider, C. (2022) BioRender.com/x46p701.

FIGURE 3

Influence of dietary factors on the risk of liver disease in individuals with the PNPLA3 I148M variant. The figure highlights the complex interaction between diet and genetic predisposition in liver disease development. The central balance illustrates the effect of PNPLA3 I148M on the liver, with steatotic liver disease (SLD) shown tipping the balance. Various dietary components are depicted around the balance, each with their respective odds ratios (OR) for influencing SLD risk. Alcohol consumption (OR = 1.04–3.0) and meat intake (OR = 1.4–3.0) increase the risk. Vegetables (OR = 0.56), coffee (OR = 0.74) and fish (OR = 0.69) are associated with a reduced risk of liver disease. The ORs were taken from Chen et al. and Oh et al. [29, 34]. Created in BioRender. Schneider, C. (2022) BioRender.com/x46p701.

FIGURE 4

Progression from a healthy liver to hepatocellular carcinoma (HCC) in the context of PNPLA3 I148M and associated risk factors. The liver disease progression includes MASLD, steatohepatitis, cirrhosis and ultimately HCC, with respective progression rates of 15%–30%, 12%–40%, 15%–25% and 7%. Characteristics associated with increased risk include genetics (OR = 1–4), age > 50 (OR = 4) and female gender (OR = 1.4). Metabolic factors include smoking (OR = 1.4), visceral fat (OR = 1.1) and insulin resistance (OR = 1.6). OR taken from Oh et al., Chalasani et al., Li et al., and Bril et al. [34, 42, 55, 80]. HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction‐associated steatotic liver disease; OR, odds ratio. Created in BioRender. Schneider, C. (2022) BioRender.com/x46p701.