Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10)) and with hepatic inflammation (P = 3.7 x 10(-4)). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
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The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which functional experiments have shown to relate to liver lipid metabolism.
“The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which have been shown through functional experiments to relate to liver lipid metabolism (24–31).”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [25]
The paper reports a strong association between PNPLA3 variation and hepatic fat content and, in its Abstract (page not given), describes published in vitro experiments showing PNPLA3 activity against triglycerides. It also says the protein’s specific role in liver lipid metabolism was unknown and that experiments on the variants identified in this study were still in progress. This source supports the PNPLA3 part of the multi-citation sentence, but not the implication that functional experiments had established its role in the liver. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPNPLA3, CPEB4, and ASPG are linked to hepatic steatosis, steatohepatitis, and/or fibrosis.
“PNPLA3, CPEB4, and ASPG, which are linked to hepatic steatosis, steatohepatitis, and/or fibrosis33,39–41”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [33]
The paper reports that a PNPLA3 variant is strongly associated with hepatic fat content and that carriers have elevated markers of liver inflammation (Abstract; page not provided). Our copy does not link CPEB4 or ASPG to these conditions, and it does not establish a PNPLA3 association with fibrosis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome of the most important human metabolic disease genes have been identified using germline genetic methods such as GWAS and whole exome sequencing.
“Some of the most important human metabolic disease genes have been identified using germline genetic methods such as GWAS and whole exome sequencing42-44.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [42]
PNPLA3 rs6006460[T] (S453I) carriers, enriched in African Americans, are associated with decreased MASLD.
“Conversely, carriers of the PNPLA3 allele rs6006460[T] (encoding S453I), enriched in African Americans, are associated with decreased MASLD (132-134).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [132]
PNPLA3 rs738409[G] (I148M) carriers are most prevalent in Hispanics and have increased susceptibility to MASLD and MASH.
“Among these polymorphisms, carriers of the Patatin Like Phospholipase Domain Containing 3 (PNPLA3) allele rs738409[G] (encoding I148M) are most prevalent in Hispanics and display an increased susceptibility to MASLD and MASH.”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [132]
The PNPLA3 polymorphism rs738409 is prevalent in the Hispanic population and is highly associated with non-alcoholic fatty liver disease.
“Use of genetic screening has identified a polymorphism rs738409 within patatin-like phospholipase domain containing 3 (PNPLA3 population or adiponutrin) that is prevalent in the Hispanic population, and is highly associated with non-alcoholic fatty liver disease.96”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [96]
The SNP rs738409 in PNPLA3 is associated with increased hepatic triglyceride content.
“In addition, we genotyped all study participants for the SNP rs738409 in the gene encoding patatin-like phospholipase domain–containing 3 (PNPLA3), which has also been shown to be associated with increased hepatic triglyceride content.11”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [11]
PNPLA3 variants have not been found to be associated with insulin resistance.
“However, in contrast to the APOC3 variants described here, the PNPLA3 variants have not been found to be associated with insulin resistance.11”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [11]
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- Authors
- Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, L. A., Boerwinkle, E., Cohen, J. C., & Hobbs, H. H.
- Affiliations
- Southern Methodist University (US)
- The University of Texas Southwestern Medical Center (US)
- Perlegen (United States) (US)
- Lawrence Berkeley National Laboratory (US)
- The University of Texas Health Science Center at Houston (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cohen, Jonathan C
- Hobbs, Helen H
- ORCID
- Venue
- Nature Genetics
- Published
- 2008-09-25
- Volume
- 40
- Issue
- 12
- Pages
- 1461-1465
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2597056
- OpenAlex
- W2017511982
- Cited by
- 3,416
- References
- 29
- Citations by year
- 2026: 174 · 2025: 230 · 2024: 212 · 2023: 240 · 2022: 250 · 2021: 295 · 2020: 313 · 2019: 197 · 2018: 219 · 2017: 189 · 2016: 194 · 2015: 189 · 2014: 156 · 2013: 141 · 2012: 135
- FWCI
- 68.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Donald W. Reynolds Foundation
- National Heart, Lung, and Blood Institute (HL-066681, HL-20948, U01HL066681, P01HL020948, RL1HL092550)
- National Institute of Diabetes and Digestive and Kidney Diseases (PL1DK081182)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- PNPLA3, non-alcoholic fatty liver disease, genetic susceptibility, hepatic fat content, liver inflammation, non-synonymous mutations, rs738409, ancestry differences, Hispanic population, African American population, European-American population, genome-wide association study
- MeSH terms
- Acyltransferases, Fatty Liver, Female, Humans, Lipase, Male, Membrane Proteins, Genetic Variation, Genetic Predisposition to Disease, Phospholipases A2, Calcium-Independent
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