Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis.

Journal

Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946

Informations de publication

Date de publication:
27 Mar 2024
Historique:
received: 15 12 2023
accepted: 11 03 2024
medline: 27 3 2024
pubmed: 27 3 2024
entrez: 27 3 2024
Statut: aheadofprint

Résumé

It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF (pwCF). We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. Whole genome sequencing was available in 4,082 pwCF with pancreatic insufficiency (n=516 with severe CFLD; n=3,566 without CFLD). We tested ~15.9 million SNPs for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including: 1) genetic variant (SERPINA1; Z-allele) previously associated with severe CFLD; 2) candidate SNPs (n=205) associated with non-CF liver diseases; 3) genome-wide association study (GWAS) of common/rare SNPs; 4) transcriptome-wide association (TWAS); and 5) gene-level and pathway analyses. The Z-allele was significantly associated with severe CFLD (p=1.1×10-4). No significant candidate SNPs were identified. GWAS identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 (p=8.05×10-10) and FNBP1 (p=4.74×10-9); suggestive, DUSP6 (p=1.51×10-7) and ANKUB1 (p=4.69×10-7)] relevant to severe CFLD pathophysiology. TWAS identified 3 genes [CXCR1 (p=1.01×10-6), AAMP (p=1.07×10-6), and TRBV24 (p=1.23×10-5)] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation and innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity, and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.

Sections du résumé

BACKGROUND AND AIMS OBJECTIVE
It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF (pwCF). We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms.
APPROACH AND RESULTS RESULTS
Whole genome sequencing was available in 4,082 pwCF with pancreatic insufficiency (n=516 with severe CFLD; n=3,566 without CFLD). We tested ~15.9 million SNPs for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including: 1) genetic variant (SERPINA1; Z-allele) previously associated with severe CFLD; 2) candidate SNPs (n=205) associated with non-CF liver diseases; 3) genome-wide association study (GWAS) of common/rare SNPs; 4) transcriptome-wide association (TWAS); and 5) gene-level and pathway analyses. The Z-allele was significantly associated with severe CFLD (p=1.1×10-4). No significant candidate SNPs were identified. GWAS identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 (p=8.05×10-10) and FNBP1 (p=4.74×10-9); suggestive, DUSP6 (p=1.51×10-7) and ANKUB1 (p=4.69×10-7)] relevant to severe CFLD pathophysiology. TWAS identified 3 genes [CXCR1 (p=1.01×10-6), AAMP (p=1.07×10-6), and TRBV24 (p=1.23×10-5)] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies.
CONCLUSION CONCLUSIONS
These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation and innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity, and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.

Identifiants

DOI: 10.1097/HEP.0000000000000863 PMID: 38536042
pubmed: 38536042
doi: 10.1097/HEP.0000000000000863
pii: 01515467-990000000-00819
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 American Association for the Study of Liver Diseases.

Auteurs

Jaclyn R Stonebraker (JR)

Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Rhonda G Pace (RG)

Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Paul J Gallins (PJ)

Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, 27695, USA.

Hong Dang (H)

Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Melis A Aksit (MA)

Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.

Anna V Faino (AV)

Children's Core for Biostatistics, Epidemiology and Analytics in Research, Seattle Children's Research Institute, Seattle, Washington, 98101, USA.

William W Gordon (WW)

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, 98195, USA.

Sonya MacParland (S)

Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

Michael J Bamshad (MJ)

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, 98195, USA.
Brotman Baty Institute for Precision Medicine, Seattle, Washington, 98195, USA.
Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA.

Ronald L Gibson (RL)

Center for Respiratory Biology & Therapeutics, Seattle Children's Research Institute, Seattle, Washington, 98105, USA.

Garry R Cutting (GR)

Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.

Peter R Durie (PR)

Fred A Wright (FA)

Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, USA.
Department of Statistics, North Carolina State University, Raleigh, North Carolina, 27695, USA.

Yi-Hui Zhou (YH)

Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, 27695, USA.
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, USA.

Scott M Blackman (SM)

Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.
Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.

Wanda K O'Neal (WK)

Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Simon C Ling (SC)

Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Michael R Knowles (MR)

Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Classifications MeSH