rs738409 — PNPLA3 I148M
Strongest genetic risk factor for non-alcoholic fatty liver disease, progression to cirrhosis, and hepatocellular carcinoma
Details
- Gene
- PNPLA3
- Chromosome
- 22
- Risk allele
- G
- Protein change
- p.Ile148Met
- Consequence
- Missense
- Inheritance
- Codominant
- Clinical
- Risk Factor
- Evidence
- Established
- Chip coverage
- v3 v4 v5
Population Frequency
Ancestry Frequencies
Related SNPs
Category
Nutrition & MetabolismThe Liver's Genetic Achilles' Heel
In 2008, a landmark genome-wide association study11 landmark genome-wide association study
Romeo et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics, 2008. The Dallas Heart Study examined hepatic fat content across 2,111 individuals of diverse ancestry using magnetic resonance spectroscopy discovered something remarkable: a single genetic variant in the PNPLA3 gene explained more variation in liver fat content than obesity, diabetes, or alcohol consumption combined. The I148M variant (rs738409) has since been validated as the strongest genetic risk factor for the entire spectrum of fatty liver disease, from simple steatosis to cirrhosis and hepatocellular carcinoma.
PNPLA3 (patatin-like phospholipase domain-containing protein 3) encodes a 481-amino acid protein also called adiponutrin. The protein localizes to the surface of lipid droplets22 lipid droplets
Lipid droplets are cellular organelles that store triglycerides and other neutral lipids. In hepatocytes, excessive lipid droplet accumulation manifests as fatty liver in liver cells and the endoplasmic reticulum, where it functions in triglyceride metabolism and lipid droplet remodeling.
The Mechanism
The I148M variant results from a C-to-G substitution at position 43,928,847 on chromosome 22, changing codon 148 from isoleucine (I) to methionine (M). This single amino acid substitution fundamentally alters how the protein behaves. The mutant 148M protein localizes more extensively to lipid droplets33 localizes more extensively to lipid droplets
Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology, 2014 than the wild-type protein and exhibits markedly reduced triglyceride hydrolase activity.
Studies using radioactive tracers demonstrate that the I148M variant slows down triglyceride hydrolysis44 slows down triglyceride hydrolysis
PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. American Journal of Physiology, 2012 during lipid depletion, essentially trapping fat in liver cells. The protein's normal function involves selectively remodeling triglycerides by incorporating and releasing specific fatty acids, but the 148M variant disrupts this delicate metabolic choreography. The result: hepatocytes accumulate lipid droplets they cannot efficiently clear, initiating a cascade that can progress from simple fat accumulation to inflammation, fibrosis, and cirrhosis.
The Evidence
The strength of association between I148M and liver disease is exceptional by genetic standards. In the original Dallas Heart Study55 original Dallas Heart Study
Romeo et al., 2008, individuals homozygous for the 148M variant (GG genotype) had more than twice the hepatic fat content of non-carriers (CC genotype). This finding has been replicated across dozens of cohorts worldwide.
A 2011 meta-analysis66 2011 meta-analysis
Sookoian & Pirola. Meta-analysis of the influence of I148M variant of PNPLA3 on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology, 2011 of 16 studies covering 3,902 patients with biopsy-proven NAFLD found that GG homozygotes had 3.24-fold higher odds of advanced necroinflammatory scores and 3.2-fold higher odds of fibrosis compared to CC individuals. Effect sizes of this magnitude are rare in common genetic variants.
The risk extends beyond fatty liver itself. A 2014 meta-analysis of cirrhosis77 2014 meta-analysis of cirrhosis
Liu et al. The rs738409 variant of the PNPLA3 gene and cirrhosis: a meta-analysis. Journal of Lipid Research, 2014 including 2,023 patients demonstrated that each copy of the G allele increases cirrhosis risk by 86% (OR 1.86, 95% CI 1.64-2.12). GG homozygotes face a more than 3-fold increased risk (OR 3.41, 95% CI 2.77-4.18) compared to CC individuals.
Perhaps most concerning, the variant substantially increases risk of hepatocellular carcinoma88 hepatocellular carcinoma
Liu et al. Association between the PNPLA3 variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology, 2013, particularly in the context of alcohol-related liver disease. Studies show GG homozygotes have approximately 4.4-fold increased HCC risk compared to non-carriers in populations with existing liver disease.
Practical Implications
The silver lining: while the I148M variant increases susceptibility to liver fat accumulation, it also appears to enhance response to intervention99 enhance response to intervention
Genetic variation in PNPLA3 confers sensitivity to weight loss-induced decrease in liver fat in humans. American Journal of Gastroenterology, 2011. GG homozygotes achieve 2.5-fold greater reductions in liver fat with low-calorie, low-carbohydrate diets compared to CC individuals. This suggests that carriers who maintain healthy body weight and limit refined carbohydrates may substantially mitigate their genetic risk.
The variant shows particularly strong gene-diet interactions1010 gene-diet interactions
Santoro et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in PNPLA3 and dietary omega-6/omega-3 PUFA intake. PLOS One, 2012. In GG carriers, hepatic fat content correlates strongly with dietary carbohydrate and sugar intake, while dietary patterns favoring omega-3 over omega-6 polyunsaturated fatty acids appear protective. Hispanic children homozygous for the 148M variant show positive correlations between liver fat and total sugar intake that aren't seen in non-carriers.
Alcohol represents a critical modifiable risk factor. Even light alcohol consumption1111 light alcohol consumption
Stickel et al. PNPLA3 rs738409, environmental factors and liver-related mortality in the US population. Journal of Hepatology, 2024 significantly amplifies the genetic risk, while coffee consumption appears protective. A 2024 population study found that drinking three or more cups of coffee daily attenuated the increased risk of liver-related mortality in G-allele carriers.
For GG homozygotes with established liver disease, enhanced surveillance may be warranted. Current hepatology guidelines recommend ultrasound screening every six months1212 ultrasound screening every six months
Liu et al. Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of NAFLD-associated hepatocellular carcinoma. Journal of Hepatology, 2014 for cirrhotic patients to enable early HCC detection, and PNPLA3 genotype may help identify high-risk individuals who benefit most from this surveillance.
Interactions
PNPLA3 I148M interacts with several other genetic variants that influence NAFLD progression:
TM6SF2 rs58542926 (E167K): The TM6SF2 variant primarily affects hepatic fat accumulation through impaired VLDL secretion, while having minimal effect on fibrosis. Combined effects studies1313 Combined effects studies
Dongiovanni et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. Journal of Lipid Research, 2017 show that individuals carrying both PNPLA3 148M and TM6SF2 167K variants have additive effects on steatosis severity. The combination confers higher liver fat content than either variant alone, though PNPLA3 remains the stronger predictor of fibrosis progression.
MBOAT7 rs641738: This variant in membrane-bound O-acyltransferase domain containing 7 associates specifically with fibrosis rather than steatosis. Individuals carrying both PNPLA3 148M and MBOAT7 risk alleles show compounded fibrosis risk1414 compounded fibrosis risk
Dongiovanni et al., 2017, suggesting these variants act on complementary pathways. MBOAT7 modulates phosphatidylinositol remodeling, while PNPLA3 affects triglyceride metabolism, but both ultimately promote hepatic inflammation and scarring.
HSD17B13 rs72613567: This splice variant produces a truncated protein and represents one of the few protective genetic factors1515 protective genetic factors
Abul-Husn et al. Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease. Hepatology International, 2021 for liver disease. HSD17B13 loss-of-function alleles reduce aminotransferases and lower risk of NASH, cirrhosis, and HCC. Critically, the protective effect of HSD17B13 variants appears to partially attenuate1616 partially attenuate
Abul-Husn et al., 2021 the increased risk conferred by PNPLA3 148M. Individuals carrying both the PNPLA3 GG genotype and HSD17B13 protective variants show intermediate disease severity compared to those with PNPLA3 GG alone.
GCKR rs780094: Variants in glucokinase regulator modestly increase liver fat through enhanced de novo lipogenesis. Epistatic analysis1717 Epistatic analysis
Méndez-Sánchez et al. Contribution of PNPLA3, GCKR, MBOAT7, NCAN, and TM6SF2 genetic variants to hepatocellular carcinoma development in Mexican patients. International Journal of Molecular Sciences, 2025 suggests a three-way interaction between PNPLA3, GCKR, and MBOAT7 that influences HCC risk, particularly in populations with high baseline NAFLD prevalence like Hispanics and Mexicans.
These gene-gene interactions explain why some individuals with PNPLA3 148M develop aggressive liver disease while others remain relatively protected. Polygenic risk scores incorporating 4-5 common variants including PNPLA3, TM6SF2, MBOAT7, and HSD17B13 show improved prediction of cirrhosis and HCC risk compared to PNPLA3 alone and may help refine clinical risk stratification.
Nutrient Interactions
Genotype Interpretations
What each possible genotype means for this variant:
Standard liver fat metabolism and lowest genetic risk for fatty liver disease
You carry two copies of the normal isoleucine variant (148I) at position 148 in the PNPLA3 gene. This represents the ancestral, fully functional version of the protein with intact triglyceride hydrolase activity. Your hepatocytes can efficiently clear lipid droplets through normal PNPLA3-mediated fat remodeling.
About 58% of individuals of European descent share this genotype. In Hispanic and Latino populations, where the 148M variant is more common, approximately 25% have the CC genotype. This genotype provides the lowest genetic risk for non-alcoholic fatty liver disease, hepatic fibrosis, and liver-related complications.
Moderately increased risk for fatty liver disease with good response to lifestyle intervention
The intermediate phenotype in CG heterozygotes reflects gene dosage effects. With one functional copy and one variant copy, approximately half of your hepatic PNPLA3 protein exhibits the 148M phenotype (lipid droplet accumulation, reduced hydrolase activity). This is sufficient to impair but not abolish normal triglyceride remodeling.
Studies using liver biopsies demonstrate that CG individuals occupy an intermediate position for all histological features of NAFLD including steatosis grade, lobular inflammation, hepatocyte ballooning, and fibrosis stage. The risk of progression to advanced liver disease is real but substantially lower than in GG homozygotes.
Importantly, research on weight loss interventions and low-carbohydrate diets shows that CG heterozygotes achieve intermediate but still substantial reductions in liver fat. You retain meaningful capacity to reverse hepatic steatosis through lifestyle modification.
Significantly increased risk for fatty liver disease, fibrosis, and hepatocellular carcinoma; highly responsive to lifestyle intervention
The homozygous 148M genotype represents complete loss of normal PNPLA3 function in triglyceride hydrolysis. All hepatic PNPLA3 protein localizes excessively to lipid droplets but cannot efficiently catalyze triglyceride breakdown during lipid depletion. This creates a metabolic bottleneck where dietary fat and de novo synthesized lipids accumulate in hepatocytes faster than they can be cleared.
The variant's impact extends beyond simple steatosis. Lipid accumulation triggers oxidative stress, lipotoxicity, and inflammatory cascades that activate hepatic stellate cells and initiate fibrosis. Over years to decades, this can progress to cirrhosis and, in a subset of individuals, hepatocellular carcinoma.
Population frequency patterns tell a story about evolutionary and environmental mismatch. The 148M variant reaches its highest frequency (0.49-0.54) in Hispanic and Native American populations, where it likely conferred metabolic advantages in ancestral environments with intermittent food availability. In modern contexts with constant access to refined carbohydrates and alcohol, the same variant becomes maladaptive.
Critically, your genetic risk is not deterministic. Liver biopsy studies show substantial heterogeneity even among GG homozygotes, with some individuals showing minimal disease while others develop advanced fibrosis. Gene-environment interactions, particularly with diet and alcohol, likely explain much of this variability. You have significant power to modify your trajectory through lifestyle choices.
Key References
Landmark 2008 Dallas Heart Study GWAS identifying PNPLA3 I148M as strongest genetic determinant of hepatic steatosis across ethnicities
Meta-analysis showing GG homozygotes have 3.24-fold increased risk of fibrosis and necroinflammation in NAFLD
Meta-analysis of 2,023 cirrhosis patients showing G allele confers 1.86-fold increased cirrhosis risk, GG vs CC OR 3.41
Individual participant meta-analysis demonstrating PNPLA3 G allele increases HCC risk in alcoholic liver disease but not HCV cirrhosis
Study confirming PNPLA3 rs738409 C>G polymorphism increases risk of NAFLD-associated hepatocellular carcinoma
Study showing GG homozygotes have 2.5-fold greater liver fat reduction with low-carb diet compared to CC genotype
2024 population study showing coffee intake ≥3 cups/day attenuates liver-related mortality risk in G-allele carriers