Association Between PNPLA3 rs738409 C&gt;G Variant and Liver-Related Outcomes in Patients With Nonalcoholic Fatty Liver Disease

Grimaudo, Stefania; Pipitone, Rosaria Maria; Pennisi, Grazia; Celsa, Ciro; Marco, V. Di; Barcellona, Maria Rosa; Boemi, Roberta; Enea, Marco; Giannetti, Aurora; Spatola, Federica; Marchesini, Giulio; Craxı̀, Antonio; Petta, Salvatore

doi:10.1016/j.cgh.2019.08.011

Cited by 115 publications

(133 citation statements)

References 30 publications

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“…Association studies have shown either no effect [ 29 , [42] , [43] , [44] ] or modest protection [ 34 ] from coronary artery disease (CAD) when comparing I148M carriers to non-carriers. Two studies that specifically matched for NAFLD presence (by histology or ultrasound) found no protection from CAD in I148M carriers [ 43 , 45 ].…”

Section: Epidemiologymentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

274

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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Section: Epidemiologymentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

274

161

View full text Add to dashboard Cite

show abstract

“…106 This single nucleotide polymorphism is strongly associated with more hepatic fat deposition and fibrosis, with recent data linking it with a higher risk of liverrelated events and death in patients with NAFLD. 107 Other approaches using plasma DNA methylation, 108 modified singlenucleotide aptamer-based assays, 109 circulating microRNA, 110 and gut microbiome metagenomic profiling, are examples of the wealth of promising data that is generated by technological advances, 111 but also highlight the need for further studies to validate these candidate NASH biomarkers. There will be issues regarding cost, reproducibility, and high-throughput capability.…”

Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

Limitations of non-invasive tests for assessment of liver fibrosis

2020

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“…Elevated risks of hepatic decompensation and liver‐related death were also associated with PNPLA3 I148M in a recent Italian prospective study 25 . PNPLA3 I148M was strongly associated with liver‐related death in an analysis of the US National Health and Nutrition Examination Survey with a median follow‐up of 23 years 28 .…”

Section: Identifying Targetable Pathways For Precision Medicinementioning

confidence: 99%

Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis

Carlsson

Lindén

Brolén

et al. 2020

Aliment Pharmacol Ther

118

107

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Background: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. Aims:To review NASH genetics and discuss the potential for precision medicine approaches to treatment. Method: PubMed search and inclusion of relevant literature. Results: Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. Conclusion:The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH. and Sanofi. Rohit Loomba is co-founder of Liponexus, Inc and has served as a speaker, a consultant or an advisory board member for

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Association Between PNPLA3 rs738409 C>G Variant and Liver-Related Outcomes in Patients With Nonalcoholic Fatty Liver Disease

Cited by 115 publications

References 30 publications

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Limitations of non-invasive tests for assessment of liver fibrosis

Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis

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