| Title: | Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease |
| Journal: | Liver International |
| Published: | 23 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37088979/ |
| DOI: | https://doi.org/10.1111/liv.15586 |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 11373
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Abstract
BACKGROUND AND AIMS: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy.</p>
METHODS: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele.</p>
RESULTS: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p < .001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p = .007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6.</p>
CONCLUSIONS: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.</p>
30 Authors
- Rosaria M. Pipitone
- Francesco Malvestiti
- Grazia Pennisi
- Oveis Jamialahmadi
- Paola Dongiovanni
- Giorgio Bertolazzi
- Jussi Pihlajamäki
- Hannele Yki-Järvinen
- Umberto Vespasiani-Gentilucci
- Federica Tavaglione
- Samantha Maurotti
- Cristiana Bianco
- Gabriele Di Maria
- Marco Enea
- Anna L. Fracanzani
- Vesa Kärjä
- Giulia Lupo
- Ville Männistö
- Marica Meroni
- Roberto Piciotti
- Sami Qadri
- Rossella Zito
- Antonio Craxì
- Vito Di Marco
- Calogero Cammà
- Claudio Tripodo
- Luca Valenti
- Stefano Romeo
- Salvatore Petta
- Stefania Grimaudo
1 Application
| Application ID | Title |
|---|---|
| 37142 | UNDERSTANDING THE GENETIC ARCHITECTURE OF CHRONIC LIVER DISEASE |
Enabling scientific discoveries that improve human health