Association of PNPLA3 rs738409 G/C gene polymorphism with nonalcoholic fatty liver disease in children: a meta-analysis

Children with obesity are at risk for numerous health problems, including nonalcoholic fatty liver disease (NAFLD). This review focuses on progress made in the epidemiology of NAFLD in children for the years 2015-2020. The estimated prevalence of NAFLD in children with obesity is 26%. The incidence of NAFLD in children has risen rapidly over the past decade. An understanding of the reasons for this rise is incomplete, but over the past 5 years, many studies have provided additional insight into the complexity of risk factors, diagnostic approaches, and associated comorbidities. Risk factors for NAFLD are wide-ranging, including perinatal factors involving both the mother and newborn, as well as environmental toxin exposure.Progress made in the noninvasive assessment will be critical to improving issues related to variability in approach to screening and diagnosis of NAFLD in children.The list of serious comorbidities observed in children with NAFLD continues to grow.Notably, for many of these conditions, such as diabetes and depression, the rates observed have exceeded the rates reported in children with obesity without NAFLD.Recent advancements reviewed show an increased awareness of this problem, while also calling attention to the need for additional research to guide successful efforts at prevention and treatment.

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“…21 Recently in children, Tang et al showed that the G allele was associated with 3 times the odds of having NAFLD compared to the C allele. 22…”

Section: Race and Ethnicitymentioning

confidence: 99%

Recent advances in the epidemiology of nonalcoholic fatty liver disease in children

2021

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“…Over the last several years, meta-analyses of PNPLA3 I148M carriers versus noncarriers repeatedly conclude that carriers of the variant allele are at increased risk for all stages of NAFLD, including NASH, cirrhosis, and HCC [6,7,65,[72][73][74][75], among the pediatric and adolescent population [2,76], and among lean individuals with NAFLD [77]. NASH is emerging as the leading cause of liver transplant in the developed world.…”

Section: Discussionmentioning

confidence: 99%

Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease

Murray

Long

Liu

et al. 2021

Nucleic Acid Therapeutics

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Human genome wide association studies confirm the association of the rs738409 single nucleotide polymorphism (SNP) in the gene encoding protein patatin like phospholipase domain containing 3 (PNPLA3) with nonalcoholic fatty liver disease (NAFLD); the presence of the resulting mutant PNPLA3 I148M protein is a driver of nonalcoholic steatohepatitis (NASH). While Pnpla3-deficient mice do not display an adverse phenotype, the safety of knocking down endogenous wild type PNPLA3 in humans remains unknown. To expand the scope of a potential targeted NAFLD therapeutic to both homozygous and heterozygous PNPLA3 rs738409 populations, we sought to identify a minor allele-specific small interfering RNA (siRNA). Limiting our search to SNP-spanning triggers, a series of chemically modified siRNA were tested in vitro for activity and selectivity toward PNPLA3 rs738409 mRNA. Conjugation of the siRNA to a triantennary N-acetylgalactosamine (GalNAc) ligand enabled in vivo screening using adeno-associated virus to overexpress human PNPLA3 I148M versus human PNPLA3 I148I in mouse livers. Structure-activity relationship optimization yielded potent and minor allele-specific compounds that achieved high levels of mRNA and protein knockdown of human PNPLA3 I148M but not PNPLA3 I148I . Testing of the minor allele-specific siRNA in PNPLA3 I148M -expressing mice fed a NASH-inducing diet prevented PNPLA3 I148Mdriven disease phenotypes, thus demonstrating the potential of a precision medicine approach to treating NAFLD.

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“…Fatty liver pathophysiology includes a well-known spectrum of determinants such as inflammation, IR, genetics and environment[ 4 , 28 , 29 ]. Genetic determinants commonly implied in NAFLD susceptibility (such as PNPLA3 [ 30 - 32 ], TM6SF2 [ 33 ], MBOAT7 [ 34 - 36 ] and HSD17B13 [ 37 - 42 ] genes) have been also linked to MAFLD pathogenesis[ 43 - 45 ] (Table 2 ). In particular, the effect of the PNPLA3 I148M polymorphism as a key genetic factor for NAFLD susceptibility across different ethnicities has been largely recognized both in adults and children[ 45 ].…”

Section: Pathophysiologymentioning

confidence: 99%

Metabolic-associated fatty liver disease from childhood to adulthood: State of art and future directions

Lanzaro¹,

Guarino²,

D'Addio³

et al. 2022

WJH

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In 2020, an international group of experts proposed to replace the term of nonalcoholic fatty liver disease with metabolic-associated fatty liver disease (MAFLD). This recent proposal reflects the close association of fatty liver with metabolic derangements, as demonstrated by previous robust data. Several factors [including genetics, inflammation, metabolic abnormalities, insulin resistance (IR), obesity, prenatal determinants, and gut–liver axis] have been found to be involved in MAFLD pathophysiology, but this tangled puzzle remains to be clearly understood. In particular, IR has been recognized as a key player in metabolic impairments development in children with fatty liver. On this ground, MAFLD definition focuses on the pathophysiological basis of the disease, by emphasizing the crucial role of metabolic impairments in this condition. Although primarily developed for adults, MAFLD diagnostic criteria have been recently updated with an age-appropriate definition for sex and age percentiles, because of the increasing attention to cardiometabolic risk in childhood. To date, accumulating evidence is available on the feasibility of MAFLD definition in clinical practice, but some data are still conflicting in highly selected populations. Considering the growing prevalence worldwide of fatty liver and its close relationship with metabolic dysfunction both in children and adults with subsequent increased cardiovascular risk, early strategies for MAFLD identification, treatment and prevention are needed. Novel therapeutic insights for MAFLD based on promising innovative biological techniques are also emerging. We aimed to summarize the most recent evidence in this intriguing research area both in children and adults.

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Association of PNPLA3 rs738409 G/C gene polymorphism with nonalcoholic fatty liver disease in children: a meta-analysis

Cited by 17 publications

References 20 publications

Recent advances in the epidemiology of nonalcoholic fatty liver disease in children

Recent advances in the epidemiology of nonalcoholic fatty liver disease in children

Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease

Metabolic-associated fatty liver disease from childhood to adulthood: State of art and future directions

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