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Your genes play a major role in whether fat quietly accumulates in your liver and whether that fat eventually causes damage. One genetic variant matters more than any other for this question: PNPLA3 I148M (patatin-like phospholipase domain-containing protein 3, isoleucine-to-methionine substitution at position 148). This single-letter change in your DNA can account for up to a quarter of the inherited risk for cirrhosis and liver cancer in the general population. Unlike most blood biomarkers, this one never changes. You test it once, and the result shapes how you think about liver health for the rest of your life.
Everyone carries two copies of the PNPLA3 gene, one from each parent. Each copy is either the common version (C) or the variant version (G). That gives you three possible results: C/C (no variant copies, baseline risk), C/G (one variant copy, moderately increased risk), or G/G (two variant copies, highest risk). Knowing which combination you carry helps you understand how aggressively to manage the metabolic factors that drive liver disease.
PNPLA3 is a protein that sits on the surface of fat droplets inside liver cells. Its normal job is to help break down stored fat so it can be exported out of the liver. The I148M variant produces a version of this protein that does the opposite of what you want: it accumulates on fat droplets and blocks the machinery that would normally clear fat out.
Specifically, the mutant protein grabs onto a helper molecule called ABHD5 that is essential for activating the liver's main fat-dismantling enzyme. With ABHD5 tied up, fat breakdown slows. At the same time, the variant impairs the liver's ability to package and export fat into the bloodstream by altering the composition of the particles that carry fat out. The result is a double hit: fat comes in at the normal rate, but both major exit routes are partially blocked.
In people who carry two copies of the variant (G/G), researchers have also found reduced energy production in liver cell mitochondria, the tiny power plants inside each cell. This is not just about fat storage. It reflects a broader shift in how the liver processes fuel, with increased production of molecules called ketones and decreased creation of new fats. These changes help explain why the G/G genotype carries the steepest risk.
The risk differences between genotypes are substantial and span the entire spectrum of liver disease, from simple fat accumulation to cancer. The following table summarizes what the research shows for each genotype.
| Who Was Studied | What Was Compared | What They Found |
|---|---|---|
| Adults screened for fatty liver disease | C/G vs. C/C for developing fatty liver | About twice the risk (roughly 2x more likely) |
| Adults screened for fatty liver disease | G/G vs. C/C for developing fatty liver | About 3.4 to 3.6 times the risk |
| Adults screened for fatty liver disease | G/G vs. C/C for developing inflammatory fatty liver (NASH) | About 4.4 times the risk |
| Adults in a large prospective study | G/G vs. C/C for liver cancer | 5 to 12 times the risk, depending on the population |
| Men in a prospective cohort | Heterozygous males vs. non-carrier females for liver cancer | About 5 times the risk |
| Homozygous carriers who were also overweight | Overweight G/G carriers vs. non-overweight non-carriers for liver cancer | About 2.9 times the risk |
Sources: Xu et al. (meta-analysis); Zhao et al. (meta-analysis); Liu et al.; Huang et al. (prospective cohort).
What this means for you: if you carry one or two copies of the G allele, the most important takeaway is that your liver is less forgiving of metabolic stress than someone with C/C. Excess weight, high blood sugar, and alcohol each amplify the risk that this variant creates. A G/G result does not guarantee liver disease, and a C/C result does not make you immune. Environmental factors remain critical. But knowing your genotype tells you how much margin for error your liver has.
The frequency of the risk allele (G) varies dramatically across populations. Hispanic and Latino individuals carry the variant most frequently, with the G allele present in roughly 47% to 52% of copies in this group. European and White populations carry it at a rate of about 15% to 23%. African American and Black populations have the lowest frequency, at roughly 13.7% to 17%. Asian and Native American populations also show high prevalence.
These population differences closely mirror the known differences in rates of inflammatory fatty liver disease and its complications across ethnic groups. If you are of Hispanic or Latino ancestry, there is a meaningfully higher chance you carry one or two copies. This is one reason genotyping can be especially informative in this group.
Because this is a genetic variant, nothing changes your genotype. But the degree to which it affects your liver depends heavily on what you do. The interaction between this gene and your environment is where actionable decisions live.
Lifestyle modification (diet and exercise): G/G carriers actually benefit the most from weight loss and dietary changes aimed at reducing liver fat. This may seem counterintuitive given that they carry the highest risk, but the data consistently show that lifestyle interventions produce larger improvements in this group than in C/C carriers. If you are G/G, aggressive attention to body composition and metabolic health is the single most impactful thing you can do.
Omega-3 fatty acids: The response to omega-3 supplementation depends on genotype, and not in the direction most people would hope. C/C carriers respond well to omega-3s for reducing liver fat. Carriers of one or two G alleles show reduced or minimal benefit. If you are G/G, omega-3 supplementation alone is unlikely to meaningfully lower your hepatic fat.
Tirzepatide (a GLP-1/GIP receptor agonist): In clinical trial data, C/C carriers achieved inflammatory fatty liver disease resolution at a rate of 94%. Carriers of the G allele showed reduced response rates. If you are considering this medication for metabolic liver disease, your genotype may help set realistic expectations.
Resmetirom (a thyroid hormone receptor agonist): Unlike tirzepatide, resmetirom's effectiveness does not appear to differ by PNPLA3 genotype. This makes it a potentially attractive option regardless of your genetic result.
PNPLA3-targeted therapies: For G/G carriers specifically, precision therapies are now in clinical trials. These include an antisense drug called AZD2693, currently in a Phase 2b trial for people with inflammatory fatty liver disease and moderate to advanced scarring who are G/G homozygotes. Early-phase trials of a related approach using small interfering RNA molecules have shown up to 40% reductions in liver fat and inflammation in homozygous carriers. These therapies work by reducing production of the harmful protein itself, which the research supports as the most logical therapeutic strategy for this variant.