Quantitative digital pathology reveals association of cell-specific PNPLA3 transcription with NAFLD disease activity

Sandhu, Bynvant; Matos, Maria C. Perez; Tran, Stephanie; Zhong, Alexander H.; Csizmadia, Eva; Kim, Misung; Herman, Mark A.; Nasser, Imad; Lai, Michelle; Jiang, Z. Gordon

doi:10.1016/j.jhepr.2019.05.007

Cited by 7 publications

(9 citation statements)

References 19 publications

(26 reference statements)

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“…We also found that a low hepatic expression of PNPLA3 mRNA was independently associated with predominant Ld-MaS vs. nil-Steatosis. PNPLA3 mRNA was not related to the PNPLA3 rs738409 variant distribution, suggesting an epigenetic reduction in the PNPLA3 function in livers predisposed to form large LDs, in agreement with a recent report in NAFLD patients [ 36 ].…”

Section: Discussionsupporting

confidence: 91%

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

Ferri

Carotti

Carpino

et al. 2021

IJMS

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In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.

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Section: Discussionsupporting

confidence: 91%

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

Ferri

Carotti

Carpino

et al. 2021

IJMS

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“… PNPLA3 encodes for an enzyme with triacylglycerol lipase and acylglycerol transacylase activities. PNPLA3 transcription rates are inversely correlated with the severity of liver fibrosis (Sandhu et al, 2019). The M allele at SNP rs738409 (p.I148M) significantly reduces PNPLA3 enzymatic activity toward glycerolipids and is strongly associated with NAFLD, alcoholic liver disease, and with cirrhosis and hepatocellular carcinoma in patients with NAFLD (The eMERGE Network, 2019).…”

Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlation in Phelan‐McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

Ricciardello

Tomaiuolo

Persico

2021

American J of Med Genetics Pt A

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Phelan‐McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2‐q13.33 terminal deletion detected in our sample of 63 PMS patients by array‐CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co‐dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype–phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence‐based genetic work‐ups, clinical assessments, and therapeutic interventions.

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“…Cirrhosis of the liver is a disorder in which the liver parenchyma is replaced with fibrous tissue and is often caused by alcoholism as well as hepatitis B and C infection (139,140). The PNPLA3 gene has been found to be associated with liver cirrhosis by multiple SNP GWAS studies (141,142) and although CNVs at PNPLA3 has not been well described or linked to Cirrhosis in the past it has been shown that transcriptional regulation of PNPLA3 has an impact on liver disease with higher levels of PNPLA3 mRNA in the cytoplasm being negatively associated with the severity of alcoholic fatty liver disease (NAFLD) in humans (143).…”

Section: First Occurrences Icd10 Code Copy Number Variation Associationsmentioning

confidence: 99%

CNest: A Novel Copy Number Association Discovery Method Uncovers 862 New Associations from 200,629 Whole Exome Sequence Datasets in the UK Biobank

Fitzgerald

Birney

2021

Preprint

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Copy number variation (CNV) has long been known to influence human traits having a rich history of research into common and rare genetic disease and although CNV is accepted as an important class of genomic variation, progress on copy number (CN) phenotype associations from Next Generation Sequencing data (NGS) has been limited, in part, due to the relative difficulty in CNV detection and an enrichment for large numbers of false positives. To date most successful CN genome wide association studies (CN-GWAS) have focused on using predictive measures of dosage intolerance or gene burden tests to gain sufficient power for detecting CN effects. Here we present a novel method for large scale CN analysis from NGS data generating robust CN estimates and allowing CN-GWAS to be performed genome wide in discovery mode. We provide a detailed analysis in the large scale UK BioBank resource and a specifically designed software package for deriving CN estimates from NGS data that are robust enough to be used for CN-GWAS. We use these methods to perform genome wide CN-GWAS analysis across 78 human traits discovering 862 genetic associations that are likely to contribute strongly to trait distributions based solely on their CN or by acting in concert with other genetic variation. Finally, we undertake an analysis comparing CNV and SNP association signals across the same traits and samples, defining specific CNV association classes based on whether they could be detected using standard SNP-GWAS in the UK Biobank.

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Quantitative digital pathology reveals association of cell-specific PNPLA3 transcription with NAFLD disease activity

Cited by 7 publications

References 19 publications

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

Genotype–phenotype correlation in Phelan‐McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

CNest: A Novel Copy Number Association Discovery Method Uncovers 862 New Associations from 200,629 Whole Exome Sequence Datasets in the UK Biobank

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