PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum

Salameh, Habeeb; Hanayneh, Muhannad Al; Masadeh, Maen; Naseemuddin, Mohammed; Matin, Tasnia; Erwin, Angelika; Singal, Ashwani K.

doi:10.14218/jcth.2016.00009

Cited by 23 publications

(13 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, our data support that more aggressive disease with higher fibrosis scores was associated with rs738409 variation–subjects with higher activity scores (A > 2) were 17 times more likely to be GG homozygous than to be homozygous for the C allele; and subjects with liver fibrosis were 7.4-fold more likely to be GG homozygous than to be CC. Lack of significant association between histological steatosis grade and rs738409 genotype was observed in at least two other case-control studies[ 46 , 47 ]; and an association between PNPLA3 and inflammation activity and fibrosis in NAFLD has also been found in other studies[ 21 , 23 , 25 ]. Our study, however, was limited by the fact that only 44% of the patients underwent liver biopsy.…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

Lisboa¹,

Nardelli²,

Pereira³

et al. 2020

WJH

View full text Add to dashboard Cite

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide, with significant morbidity associated with nonalcoholic steatohepatitis (NASH). Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression. AIM To investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients. METHODS This cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil. The case patients ( n = 148) were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease. According to the clinical protocol, patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis ( n = 65). Steatohepatitis was confirmed in 54 patients. Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis ( n = 94). The control group ( n = 137) was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests. All individuals underwent PNPLA3 and TM6SF2 genotype analysis. RESULTS PNPLA3 CC, CG and GG genotype frequencies were 37%, 44% and 19%, respectively, in NAFLD patients and were 58%, 31% and 10% in controls ( P < 0.001). In a model adjusted for gender, age, body mass index and type 2 diabetes mellitus, the G allele increased the chance of NAFLD (OR = 1.69, 95%CI: 1.21-2.36, P = 0.002) and NASH (OR = 3.50, 95%CI: 1.84-6.64, P < 0.001). The chance of NASH was even higher with GG homozygosis (OR = 5.53, 95%CI: 2.04-14.92, P = 0.001). No association was found between G allele and the features of metabolic syndrome. In histological assessment, PNPLA3 genotype was not associated with steatosis grade, although GG homozygosis increased the chance of significant NASH activity (OR = 17.11, 95%CI: 1.87-156.25, P = 0.01) and fibrosis (OR = 7.42, 95%CI: 1.55-34.47, P = 0.01) in the same adjusted model. TM6SF2 CC, CT and TT genotype frequencies were 83%, 15% and 0.7%, respectively, in NAFLD patients and were 84%, 16% and 0.7% in controls ( ...

show abstract

Section: Discussionmentioning

confidence: 83%

“…The first GWA study in NAFLD identified a single highly significant association between increased hepatic TG content and the PNPLA3 [ 17 ]. Subsequent studies demonstrated that this variant was also associated with the progression of NAFLD in different ethnic populations around the world[ 21 , 25 , 26 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

Lisboa¹,

Nardelli²,

Pereira³

et al. 2020

WJH

View full text Add to dashboard Cite

show abstract

“…This effect seems to be more pronounced in normal-weight subjects than in overweight subjects [ 54 , 55 ]. The PNPLA3 variant allele rs738409 C>G has been associated with the risk and severity of NAFLD (inflammation, and progression to fibrosis) and even with HCC development [ 56 ]. PNPLA3 is a strong modifier of the natural history of NAFLD and can be considered as a potential target for therapy.…”

Section: Pathophysiological and Molecular Mechanisms Of Non-alcohomentioning

confidence: 99%

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Mazzolini

Sowa

Atorrasagasti

et al. 2020

Cells

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)—the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.

show abstract

“…Patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) genetic variant is the strongest genetic risk factor for the development of NASH ( 17 ). Indeed, studies have shown that individuals carrying the PNPLA3 (rs738409) variant have about a threefold increased likelihood of having NASH ( 18 – 20 ). Moreover, single-nucleotide polymorphisms (SNPs) in the transmembrane 6 superfamily member 2 ( TM6SF2 rs58542926), membrane-bound O-acyltransferase domain containing 7 ( MBOAT7 rs641738), and 17-beta-hydroxysteroid dehydrogenase 13 ( HSD17B13 rs72613567) genetic variants are also associated with greater susceptibility to NASH ( 21 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

Individualized Polygenic Risk Score Identifies NASH in the Eastern Asia Region: A Derivation and Validation Study

Gao

Zheng

Chen

et al. 2021

Clin Transl Gastroenterol

View full text Add to dashboard Cite

INTRODUCTION: Strong evidence indicates that multiple genetic and environmental risk factors play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). We aimed to develop and validate a novel nomogram, incorporating both genetic and clinical factors, for predicting NASH. METHODS: A total of 1,070 Asian individuals with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) from 2 countries (China and South Korea) were recruited. The histological spectrum of NAFLD was classified according to the NASH clinical research network scoring system. The nomogram was developed in the Chinese training set (n = 402), and then, it was validated in both the Chinese internal validation set (n = 136) and the external Korean validation cohort (n = 532), respectively. RESULTS: Sex, metabolic syndrome, insulin resistance, serum aspartate aminotransferase levels, and PNPLA3 (rs738409) and HSD17B13 (rs72613567) genetic variants were strongly associated with NASH. Based on their regression coefficients, we developed a nomogram with good discriminatory ability (area under the receiver operating characteristic curve: 0.81, 95% confidence interval [CI] 0.77–0.85) and good calibration (Hosmer-Lemeshow test, P = 0.794) for identifying NASH. In the 2 validation cohorts, the nomogram showed high area under the receiver operating characteristic curves (internal validation set: 0.80, 95% CI 0.72–0.88; external validation cohort: 0.76, 95% CI 0.72–0.80) and good calibration. DISCUSSION: Our newly developed and externally validated nomogram, incorporating both genetic and clinical risk factors, may be conveniently used to predict NASH. Further validation studies in other ethnic groups are warranted to confirm its diagnostic utility to identify NASH, among patients with biopsy-proven NAFLD.

show abstract

PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum

Cited by 23 publications

References 75 publications

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Individualized Polygenic Risk Score Identifies NASH in the Eastern Asia Region: A Derivation and Validation Study

Contact Info

Product

Resources

About