The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Romeo, Stefano; Sentinelli, Federica; Cambuli, Valentina M.; Incani, Michela; Congiu, Tiziana; Matta, Vanessa; Pilia, Sabrina; Huang-Doran, Isabel; Cossu, Efisio; Loche, Sandro; Baroni, Marco Giorgio

doi:10.1016/j.jhep.2010.02.034

Cited by 147 publications

(127 citation statements)

References 28 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…In Finnish population with NAFLD, the G allele was found to be significantly associated with increased AST levels, however in Hispanics [5] and in an Italian population [32], it was associated with increased serum ALT levels only. Increased serum levels of both ALT and AST were observed in various populations including the Argentinian [7], Italian [39], Japanese [37] and the Taiwanese [38]. Many factors such as ethnicity, the age group, presence of obesity and/or diabetes could have attributed to the differences in these findings in the various studies.…”

Section: Discussionmentioning

confidence: 97%

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

Hegazy¹,

Samie²,

Ezzat³

et al. 2016

OJGas

View full text Add to dashboard Cite

Introduction: There is growing evidence that genetic and environmental factors play an important role in the development and progression of non-alcoholic fatty liver disease (NAFLD). We investigated the association of single nucleotide polymorphism (SNP) rs738409 in PNPLA3 gene and TNF-α G238A polymorphism with the development and severity of NAFLD in an overweight and obese Egyptian population. Material and Methods: 100 overweight and obese patients with NAFLD and 30 control subjects were enrolled. All NAFLD patients underwent a confirmatory biopsy. Laboratory investigations included fasting plasma glucose, kidney and liver function tests, liver enzymes, lipid profile and hepatitis markers. Abdominal ultrasound was performed and all subjects were genotyped for (rs738409) PNPLA3 and (rs361525) TNF-α gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results: The homozygous GG genotype of the PNPLA3 was most frequent among patients with NASH (26%) as compared to borderline NASH (20.5%) and simple steatosis (20%). Higher serum levels of transaminases were observed in NAFLD patients and controls who were carriers of the G allele of rs738409, but this was not statistically significant. Regarding the TNF-α G238A SNP; the frequency of the A allele was significantly higher in NAFLD patients (20%) compared to controls (5%) (p value = 0.006). The highest TNF G allele frequency was observed in the NASH group (88%) and this was statistically significant (p value = 0.009). Conclusion: Our study confirmed the association of the PNPLA3 (rs738409) and TNF-α promoter region G238A polymorphisms with susceptibility to NAFLD and its progression. M. A. Hegazy et al.54

show abstract

Section: Discussionmentioning

confidence: 97%

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

Hegazy¹,

Samie²,

Ezzat³

et al. 2016

OJGas

View full text Add to dashboard Cite

show abstract

“…Substantial data support an important role for PNPLA3 in normal metabolism and disease including the following: i ) PNPLA3 shares signifi cant homology with proteins known to play critical roles in metabolism ( 9,64,65 ); ii ) PNPLA3 is highly regulated by important nutritional/metabolic factors ( 25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42); iii ) PNPLA3 expression is altered in obese/dysmetabolic states ( 25,(27)(28)(29); iv ) PNPLA3 has lipid hydrolase and transacylase activities in vitro ( 28,43,44 ); and v ) Genetic variation in PNPLA3 is associated with NAFLD in humans (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Despite this strong evidence, the in vivo function and physiological relevance of PNPLA3 remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, genetic variation in the human PNPLA3 gene (i.e., the rs738409 I148M allele in particular) has been strongly and repeatedly associated with hepatic TAG content, hepatocellular injury, and progression of NAFLD in humans (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). PNPLA3 variants have also been associated with obesity and features of the metabolic syndrome in humans in several studies ( 16,25,26 ), although subsequent studies have not confi rmed this association ( 10,12,18,22 ).…”

Section: Animalsmentioning

confidence: 99%

“…Nevertheless, numerous studies have demonstrated a strong association between genetic variation in PNPLA3 and hepatic steatosis, hepatic injury, and progression of NAFLD (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The human rs738409 variant is of particular interest because it contains a C → G nucleotide change that encodes a methionine in place of isoleucine at position 148 (the I148M mutation).…”

Section: Global Pnpla3 Deletion Promotes Compensatory Regulation Of Pmentioning

confidence: 99%

See 1 more Smart Citation

Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

Basantani

Sitnick

Cai

et al. 2011

Journal of Lipid Research

209

175

View full text Add to dashboard Cite

Obesity and the metabolic syndrome are major contributors to morbidity and mortality from a variety of diseases affecting virtually all organ systems ( 1 ). Obesity is essentially a disorder of lipid accumulation, primarily in the form of triacylglycerols (TAGs) in adipose tissue. TAGs serve as a critical reservoir for lipid metabolites involved not only in energy homeostasis but also other essential cellular processes including membrane synthesis and cell signaling. In the context of chronic energy excess and/or impaired lipid metabolism, TAGs accumulate in metabolically relevant nonadipose tissues such as liver, where they are associated with cellular and systemic Abstract PNPLA3 (adiponutrin, calcium-independent phospholipase A 2 epsilon [iPLA 2 ]) is an adipose-enriched, nutritionally regulated protein that belongs to the patatinlike phospholipase domain containing (PNPLA) family of lipid metabolizing proteins. Genetic variations in the human PNPLA3 gene (i.e., the rs738409 I148M allele) has been strongly and repeatedly associated with fatty liver disease. Although human PNPLA3 has triacylglycerol (TAG) hydrolase and transacylase activities in vitro, its in vivo function and physiological relevance remain controversial. The objective of this study was to determine the metabolic consequences of global targeted deletion of the Pnpla3 gene in mice. We found that Pnpla3 mRNA expression is altered in adipose tissue and liver in response to acute and chronic nutritional challenges. However, global targeted deletion of the Pnpla3 gene in mice did not affect TAG hydrolysis, nor did it infl uence energy/glucose/lipid homoeostasis or hepatic steatosis/injury. Experimental interventions designed to increase Pnpla3 expression (refeeding, high-sucrose diet, diet-induced obesity, and liver X receptor agonism) likewise failed to reveal differences in the above-mentioned metabolic phenotypes. Expression of the Pnpla3 paralog, Pnpla5 , was increased in adipose tissue but not in liver of Pnpla3 -defi cient mice, but compensatory regulation of genes involved in TAG metabolism was not identifi ed. Together these data argue against a role for Pnpla3 loss-of-function in fatty liver disease or metabolic syndrome in mice. -Basantani,

show abstract

“…Association of 1148M variant with the disease progress to liver cancer and also shows the impact of this variant in the inflammation and exacerbation of the disease (60,63,65). Association between this variant, steatosis, and the levels of liver enzymes were observed in children with obesity in different races (67)(68)(69).…”

Section: Genetic Analysismentioning

confidence: 88%

Which Method is Superior in the Diagnosis of Nonalcoholic Fatty Liver and Steatohepatatis in Children?

et al. 2017

View full text Add to dashboard Cite

Context: Nonalcoholic fatty liver disease (NAFLD) is increasing with the increased rate of obesity and reduced physical activity in children worldwide. Despite high prevalence of the disease, a standard and acceptable diagnostic method is not available. The current study aimed at collecting all related articles and evaluating the challenges. Methods:The current study searched Scopus, Web of Science, and PubMed. Articles and guidelines in English in the field of invasive and noninvasive diagnostic methods for NAFLD and nonalcoholic steatohepatitis (NASH) in children and adolescents up to Oct 2016 were used. It was tried to evaluate all laboratory and radiologic methods, biomarkers, and scores in addition to mention the challenges.Results: Ultrasonography and laboratory evaluation, which were routine methods in early diagnosis, did not have enough accuracy in this field. Diagnosis of steatosis and fibrosis and determining the severity of disease were achieved by fibro scan and controlled attenuation parameter (CAP) without the challenges of computed tomography (CT) scan and magnetic resonance imaging (MRI). Fatty liver can be predicted with high accuracy by body analyzer, anthropometric, and DEXA methods.Conclusions: Diagnosis and prediction of fatty liver should be done in all children with obesity aged > 3 years, and physician should seek the genetic and metabolic causes in children aged < 3 years and/or without overweight.

show abstract

The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Cited by 147 publications

References 28 publications

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

Which Method is Superior in the Diagnosis of Nonalcoholic Fatty Liver and Steatohepatatis in Children?

Contact Info

Product

Resources

About

The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Cited by 147 publications

References 28 publications

PNPLA3 and TNF-&lt;i&gt;α&lt;/i&gt; G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

PNPLA3 and TNF-&lt;i&gt;α&lt;/i&gt; G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

Which Method is Superior in the Diagnosis of Nonalcoholic Fatty Liver and Steatohepatatis in Children?

Contact Info

Product

Resources

About

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD