Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility

Xia, Yan; Huang, Chunxia; Li, Guangyi; Chen, Kaihua; Han, Li; Tang, Liang; Luo, Huaiqing; Bao, Meihua

doi:10.1016/j.clinre.2019.01.008

Cited by 29 publications

(22 citation statements)

References 28 publications

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“…TM6SF2 variants have a moderate to large effect on the risk of NAFLD, 36,38 with the 167K allele having an allelic odds ratio of 1.82 for steatosis (Table 1). 39 Consistent with these findings, the 167EE homozygous ancestral genotype was associated with a significantly reduced risk of NAFLD in recent meta‐analyses 39,40 . The TM6SF2 E167K allele has a frequency of 7% in the 1000 Genomes Project phase 3 combined population (Table 1).…”

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

110

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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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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

110

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“…In line with this possibility, genetics studies in Caenorhabditis elegans suggest that PI acyl-chains affect PI 3-phosphate signaling ( 98 ). Genetic variants of MBOAT7 in humans are reported to affect nonalcoholic fatty liver disease, but inconsistencies are also suggested ( 107 ). In mice, liver-specific MBOAT7 knockdown or knockout promotes fatty liver ( 108 , 109 ).…”

Section: Membrane Pufasmentioning

confidence: 99%

Roles of polyunsaturated fatty acids, from mediators to membranes

Harayama

Shiraishi

2020

Journal of Lipid Research

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Polyunsaturated fatty acids (PUFAs), such as arachidonic acid and docosahexaenoic acid, are recognized as important biomolecules, but understanding their precise roles and modes of action remains challenging. PUFAs are precursors for a plethora of signaling lipids, for which knowledge about synthetic pathways and receptors has accumulated. However, due to their extreme diversity and the ambiguity concerning the identity of their cognate receptors, the roles of PUFA-derived signaling lipids require more investigation. In addition, PUFA functions cannot be explained just as lipid mediator precursors, since they are also critical for the regulation of membrane biophysical properties. The presence of PUFAs in membrane lipids also affects the functions of transmembrane proteins and peripheral membrane proteins. Although the roles of PUFAs as membrane lipid building blocks were difficult to analyze, the discovery of lysophospholipid acyltransferases, which are critical for their incorporation, advanced our understanding. Recent studies unveiled how lysophospholipid acyltransferases affect PUFA levels in membrane lipids, and their genetic manipulation became an excellent strategy to study the roles of PUFA-containing lipids. In this review, we will provide an overview of metabolic pathways regulating PUFAs as lipid mediator precursors and membrane components, and update recent progress about their functions. Some issues to be solved for future research will also be discussed.

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“…However, the association between the rs641738 variant and liver injuries remains still controversial and not fully replicated, mainly due to the different sample size, clinical features and severity of the disease ( i.e. obesity and T2D presence), and ethnicity of the cohorts enrolled in the studies or to the diverse assessment of hepatic steatosis [50] , [51] , [52] , [53] , [54] . In particular, the T allele frequency in different ethnicity is highly variable ranging from 0.44 in Europeans, 0.32 in African-Americans and 0.34 in Hispanics and displays even intra-ethnic variability (0.24 in East Asians compared to 0.53 in those of South Asian ancestry).…”

Section: The Rs641738 Variant Is Considered a Risk Factor For Mafld Omentioning

confidence: 99%

MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD

2020

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Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.

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Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility

Cited by 29 publications

References 28 publications

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

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

Roles of polyunsaturated fatty acids, from mediators to membranes

MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD

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