Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

doi:10.1038/NG.257

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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Journal Article•DOI•

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Stefano Romeo¹, Julia Kozlitina², Julia Kozlitina¹, Chao Xing¹, Alexander Pertsemlidis¹, David Cox, Len A. Pennacchio³, Len A. Pennacchio⁴, Eric Boerwinkle⁵, Jonathan C. Cohen¹, Helen H. Hobbs¹ - Show less +7 more•Institutions (5)

University of Texas Southwestern Medical Center¹, Southern Methodist University², United States Department of Energy³, Lawrence Berkeley National Laboratory⁴, University of Texas Health Science Center at Houston⁵

25 Sep 2008-Nature Genetics (Nature Publishing Group)-Vol. 40, Iss: 12, pp 1461-1465

TL;DR: Variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

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Abstract: 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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Journal Article•DOI•

Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.

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G. Vernon¹, G. Vernon², Ancha Baranova¹, Ancha Baranova³, Zobair M. Younossi², Zobair M. Younossi¹ - Show less +2 more•Institutions (3)

Inova Health System¹, Inova Fairfax Hospital², George Mason University³

01 Aug 2011-Alimentary Pharmacology & Therapeutics

TL;DR: Aliment Pharmacol Ther 2011; 34: 274–285

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Abstract: SUMMARY Background Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, and its worldwide prevalence continues to increase with the growing obesity epidemic. This study assesses the epidemiology of NAFLD in adults based on clinical literature published over the past 30 years. Aim To review epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults based on clinical literature published over the past 30 years. Methods An in-depth search of PubMed (1980–2010) was based on five search terms: ‘nonalcoholic fatty liver disease’ OR ‘non-alcoholic steatohepatitis’ OR ‘fatty liver’ OR ‘steatosis’ AND ‘incidence’ [MeSH Terms] OR ‘prevalence’ [MeSH Terms] OR ‘natural history’. Studies of paediatric cohorts were excluded. Articles were categorised by topic and summarised, noting generalisations concerning their content.

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2,679 citations

Cites background from "Genetic variation in PNPLA3 confers..."

...A regression analysis indicates that these two sequence variations account for 72% of the observed ethnic differences in hepatic fat content in the study cohort.(71) In addition, resequencing of the PNPLA3 gene in individuals with abnor-...
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...72 In homozygous carriers of this allele, hepatic fat content is more than twofold higher than in noncarriers.(71) Notably, this allele is most prevalent in Hispanics (0....
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...mally high liver fat content revealed three cases of null mutations, which is consistent with the idea that a loss-offunction of PNPLA3 causes hepatic steatosis.(71)...
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Journal Article•DOI•

Mechanisms of NAFLD development and therapeutic strategies

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Scott L. Friedman¹, Brent A. Neuschwander-Tetri², Mary E. Rinella³, Arun J. Sanyal⁴•Institutions (4)

Icahn School of Medicine at Mount Sinai¹, Saint Louis University², Northwestern University³, Virginia Commonwealth University⁴

02 Jul 2018-Nature Medicine

TL;DR: Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression are discussed.

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Abstract: There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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2,004 citations

Journal Article•DOI•

NAFLD: A multisystem disease

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Christopher D. Byrne¹, Christopher D. Byrne², Giovanni Targher•Institutions (2)

National Institute for Health Research¹, University of Southampton²

01 Apr 2015-Journal of Hepatology

TL;DR: A narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease and the factors linkingNAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD.

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1,897 citations

Journal Article•DOI•

Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis†

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Herbert Tilg¹, Alexander R. Moschen¹•Institutions (1)

Innsbruck Medical University¹

01 Nov 2010-Hepatology

TL;DR: Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

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1,882 citations

Cites background from "Genetic variation in PNPLA3 confers..."

...Besides the well-established lipogenesis-controlling factors such as sterol regulatory element-binding protein (SREBP) or carbohydrate response element-binding protein (ChREBP), X-box binding protein 1 (XBP1), known as a key regulator of the unfolded protein response (UPR) secondary to ER stress, is a only recently characterized regulator of hepatic lipogenesis.13 Triglycerides are the main lipids stored in the liver of patients with NAFLD....
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...Whereas genetic factors overall may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a more progressive disease course in NAFLD....
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...Whereas genetic factors overall may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a more progressive disease course in NAFLD.(97) Many of the events discussed here might often take place rather in parallel than consecutively, therefore not allowing the exact dissection of the evolution of steatosis and inflammation....
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...Polymorphisms in patatinlike phospholipase 3 (PNPLA3), encoding a protein of unknown function with homology to lipid acyl hydrolases, has been strongly associated with increased hepatic fat content in NAFLD.(97) Several other genetic variants have been identified, although with less convincing evidence, except for apolipoprotein C3....
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...Because a highfat diet is needed in almost all experimental models to induce pathology, it is evident that dietary factors and nutrient sensing are cornerstones of these diseases.113 Whereas genetic factors overall may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a more progressive disease course in NAFLD.97 Many of the events discussed here might often take place rather in parallel than consecutively, therefore not allowing the exact dissection of the evolution of steatosis and inflammation....
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Journal Article•DOI•

Mechanisms for insulin resistance: common threads and missing links.

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Varman T. Samuel¹, Gerald I. Shulman¹•Institutions (1)

Yale University¹

02 Mar 2012-Cell

TL;DR: This work has shown that changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition may converge to promote the accumulation of specific lipid metabolites in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance.

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1,831 citations

Cites background from "Genetic variation in PNPLA3 confers..."

...Recently, genome-wide array screens have associated NAFLD with a relatively common single-nucleotide polymorphism, rs738409, in the gene encoding the lipid droplet protein patatin-like phospholipase domaincontaining protein 3 (PNLPA3) (Romeo et al., 2008)....
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References

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Journal Article•DOI•

Inference of Population Structure Using Multilocus Genotype Data: Linked Loci and Correlated Allele Frequencies

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Daniel Falush¹, Matthew Stephens², Jonathan K. Pritchard³•Institutions (3)

Max Planck Society¹, University of Washington², University of Chicago³

01 Aug 2003-Genetics

TL;DR: Extensions to the method of Pritchard et al. for inferring population structure from multilocus genotype data are described and methods that allow for linkage between loci are developed, which allows identification of subtle population subdivisions that were not detectable using the existing method.

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Abstract: We describe extensions to the method of Pritchard et al. for inferring population structure from multilocus genotype data. Most importantly, we develop methods that allow for linkage between loci. The new model accounts for the correlations between linked loci that arise in admixed populations (“admixture linkage disequilibium”). This modification has several advantages, allowing (1) detection of admixture events farther back into the past, (2) inference of the population of origin of chromosomal regions, and (3) more accurate estimates of statistical uncertainty when linked loci are used. It is also of potential use for admixture mapping. In addition, we describe a new prior model for the allele frequencies within each population, which allows identification of subtle population subdivisions that were not detectable using the existing method. We present results applying the new methods to study admixture in African-Americans, recombination in Helicobacter pylori , and drift in populations of Drosophila melanogaster . The methods are implemented in a program, structure , version 2.0, which is available at http://pritch.bsd.uchicago.edu.

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7,615 citations

Journal Article•DOI•

Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity

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Jeffrey D. Browning, Lidia S. Szczepaniak¹, Robert L. Dobbins, Pamela Nuremberg², Jay D. Horton, Jonathan Cohen, Scott M. Grundy³, Helen H. Hobbs⁴ - Show less +4 more•Institutions (4)

University of Texas Southwestern Medical Center¹, Texas Scottish Rite Hospital for Children², Veterans Health Administration³, Howard Hughes Medical Institute⁴

01 Dec 2004-Hepatology

TL;DR: The prevalence of hepatic steatosis was greater in men than women among whites, but not in blacks or Hispanics, and significant ethnic and sex differences in the prevalence may have a profound impact on susceptibility to Steatosis‐related liver disease.

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3,429 citations

Journal Article•DOI•

The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study

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Leon A. Adams¹, James F. Lymp¹, Jenny St. Sauver¹, Schuyler O. Sanderson¹, Keith D. Lindor¹, Ariel E. Feldstein¹, Paul Angulo¹ - Show less +3 more•Institutions (1)

Mayo Clinic¹

01 Jul 2005-Gastroenterology

TL;DR: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis, although the absolute risk is low.

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2,681 citations

Journal Article•DOI•

Molecular mediators of hepatic steatosis and liver injury

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Jeffrey D. Browning¹, Jay D. Horton•Institutions (1)

University of Texas Southwestern Medical Center¹

15 Jul 2004-Journal of Clinical Investigation

TL;DR: Recent advances in the understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis are highlighted.

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Abstract: Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.

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1,904 citations

"Genetic variation in PNPLA3 confers..." refers background in this paper

...The accumulation of excess triglyceride in the liver, a condition known as hepatic steatosis (or fatty liver), is associated with adverse metabolic consequences, including insulin resistance and dyslipidemi...
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Journal Article•DOI•

Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population

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Lidia S. Szczepaniak¹, Pamela Nurenberg¹, David Leonard, Jeffrey D. Browning¹, Jason S. Reingold¹, Scott M. Grundy¹, Helen H. Hobbs¹, Robert L. Dobbins¹ - Show less +4 more•Institutions (1)

University of Texas Southwestern Medical Center¹

01 Feb 2005-American Journal of Physiology-endocrinology and Metabolism

TL;DR: MRS provides a sensitive, quantitative, noninvasive method to measure HTGC and, when applied to a large urban US population, revealed a strikingly high prevalence of hepatic steatosis.

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Abstract: Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the criteria used to diagnose the disorder remain poorly defined. Localized proton magnetic resonance spectroscopy (MR...

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1,457 citations