Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphic (rs738409) single nucleotide polymorphisms and susceptibility to nonalcoholic fatty liver disease: A meta-analysis of twenty studies

Zhao, Yan; Zhao, Wenli; Ma, Jinghong; Toshiyoshi, Maeda; Zhao, Ye

doi:10.1097/md.0000000000033110

Cited by 4 publications

(3 citation statements)

References 52 publications

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“…Previous meta-analyses have consistently shown an association between the PNPLA3 G allele and the onset/severity of MASLD. 22,23 However, these meta-analyses mainly evaluated PNPLA3 variant-related associations without adopting formal adequate inclusion criteria to minimize the risk of selection bias. Compared with these meta-analyses, we used stringent inclusion criteria for MASLD patients and analyzed more studies.…”

Section: Discussionmentioning

confidence: 99%

“…3 Recent advances have shed light on genetic variations linked to MASLD, 4 with a spotlight on the rs738409 C > G (p.I148M) single nucleotide polymorphism in the patatin-like phospholipase domain-containing protein-3 (PNPLA3) gene, identi ed as a prominent genetic risk factor across the spectrum of MASLD. [5][6][7] In particular, the interplay of this genetic factor with both treatment and environmental factors has attracted considerable scienti c interest 8,9 in a discussion centered on the potential usefulness of PNPLA3 genotyping to guide MASLD management. 10 Despite these advances, the genetic epidemiology of PNPLA3 in MASLD patients and the extent of its impact on disease phenotype, as well as potential variations due to environmental factors, remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Global epidemiology and implications of PNPLA3 I148M variant in MASLD: a systematic review and meta-analysis

Souza,

Al-Sharif,

Diaz

et al. 2024

Preprint

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Background and Aims: PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD. Methods PubMed and Embase were searched until December 2023 for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalised linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analysed using the DerSimonian-Laird method. Subgroup, meta-regression and sensitivity analyses were also performed. PROSPERO registration number: CRD42023449838. Results We identified 109 studies (118,302 MASLD individuals) with an overall minor allele frequency of the G allele at PNPLA3 [MAF(G)] of 0.45 (95%CI 0.43; 0.48, I²=98%), adjusted to 0.39 (95%CI 0.36; 0.43, I²=98%) due to publication bias. The highest MAF(G) was found in Latin America and the lowest in Europe. No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism and worse liver damage/histology than non-carriers. Additionally, only the PNPLA3 GG genotype was associated with mortality and liver-related events. Meta-regressions showed the influence of adiposity, age, diabetes mellitus and glucose on PNPLA3 expression. Conclusions This study reveals the global pattern of PNPLA3 and its clinical, histological and outcomes implications in MASLD. Our findings underscore the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches. Further research is needed on the genetic epidemiology of underrepresented populations, challenges of incorporating genotyping into clinical practice and gene-environment interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Global epidemiology and implications of PNPLA3 I148M variant in MASLD: a systematic review and meta-analysis

Souza,

Al-Sharif,

Diaz

et al. 2024

Preprint

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“…This variation in disease progression suggests genetic predispositions and, indeed, studies have shown that genetic factors play a role in NAFLD pathogenesis 12 13 . Although a polygenic disease, common genetic variants have been consistently associated with increased risk of steatosis, particularly small nucleotide polymorphisms (SNPs) in Patatin-like phospholipase domain-containing protein 3 ( PN P LA3 ), Lysophospholipase-like 1 ( LYPLAL1 ), protein phosphatase 1 regulatory subunit 3B ( PPP1R3B ), Neurocan ( NCAN ) and glucokinase regulator ( GCKR ) 14 15 16 . However, an accumulation of fat is not the only risk factor for promoting the transition from non-alcoholic fatty liver to NASH, a central component is persistent inflammation 4,5 .…”

Section: Introductionmentioning

confidence: 99%

RNAseq analysis reveals transcriptome changes associated with the progression of non-alcoholic liver disease in livers fromEfcab4bknockout mice

Cheng,

Pedicini,

Morales Alcala

et al. 2024

Preprint

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EFCAB4B is an evolutionarily conserved protein that encodes for the Rab GTPase Rab46, and the CRAC channel modulator, CRACR2A. Previous genome wide association studies have demonstrated the association of EFCAB4B variants in the progression of non-alcoholic liver disease (NAFLD). In this study we show that mice with global depletion of Efcab4b-/- have significantly larger livers than their wild-type (WT) counterparts. We performed RNA-sequencing (RNA-seq) analysis with liver tissues to investigate differential global gene expression among Efcab4b-/- and WT mice. Of the 69 differentially expressed genes (DEGs), analyses of biological processes found significant enrichment in liver and bile development, with 6 genes (Pck1, Aacs, Onecut1, E2f8, Xbp1, and Hes1) involved in both processes. Specific consideration of possible roles of DEGs or their products in NAFLD progression to (NASH) and hepatocarcinoma (HCC), demonstrated DEGs in the livers of Efcab4b-/- mice had roles in molecular pathways including lipid metabolism, inflammation, ER stress, and fibrosis. The results in this study provide additional insights into molecular mechanisms responsible for increasing susceptibility of liver injuries associated with EFCAB4B.

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PNPLA3 as a driver of steatotic liver disease: navigating from pathobiology to the clinics via epidemiology

Weiskirchen,

Lonardo

2024

J Transl Genet Genom

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Steatotic liver disease (SLD), particularly metabolic dysfunction-associated SLD, represents a significant public health concern worldwide. Among the various factors implicated in the development and progression of this condition, the patatin-like phospholipase domain-containing protein 3 (PNPLA3 ) gene has emerged as a critical player. Variants of PNPLA3 are associated with altered lipid metabolism, leading to increased hepatic fat accumulation and subsequent inflammation and fibrosis. Understanding the role of PNPLA3 not only enhances our comprehension of the pathomechanisms driving SLD but also informs potential therapeutic strategies. The molecular mechanisms through which PNPLA3 variants contribute to lipid dysregulation and hepatocyte injury in SLD are critically discussed in the present review article. We extensively analyze clinical cohorts and population-based studies underpinning the association between PNPLA3 polymorphisms and the risk of developing SLD, and its liver-related and protean extrahepatic outcomes, in concert with other risk modifiers, notably including age, sex, and ethnicity in adults and children. We also discuss the increasingly recognized role played by the PNPLA3 gene in liver transplantation, autoimmune hepatitis, and acquired immunodeficiency syndrome. Finally, we examine the clinical implications of PNPLA3 diagnostics regarding risk stratification and targeted therapies for patients affected by SLD in the context of precision medicine approaches.

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Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphic (rs738409) single nucleotide polymorphisms and susceptibility to nonalcoholic fatty liver disease: A meta-analysis of twenty studies

Abstract: Background: To investigate the correlation between rs738409 polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (encoding I148m) and genetic susceptibility to nonalcoholic fatty liver disease (NAFLD).

Cited by 4 publications

References 52 publications

Global epidemiology and implications of PNPLA3 I148M variant in MASLD: a systematic review and meta-analysis

Global epidemiology and implications of PNPLA3 I148M variant in MASLD: a systematic review and meta-analysis

RNAseq analysis reveals transcriptome changes associated with the progression of non-alcoholic liver disease in livers fromEfcab4bknockout mice

PNPLA3 as a driver of steatotic liver disease: navigating from pathobiology to the clinics via epidemiology

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