Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis-Reference-Cited by-同舟云学术

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

Published:2024-03-27 Issue: Volume: Page:
ISSN:0270-9139
Container-title:Hepatology
language:en
Short-container-title:

Author:

Stonebraker Jaclyn R.¹^ORCID,Pace Rhonda G.¹^ORCID,Gallins Paul J.²^ORCID,Dang Hong¹,Aksit Melis A.³^ORCID,Faino Anna V.⁴^ORCID,Gordon William W.⁵^ORCID,MacParland Sonya⁶,Bamshad Michael J.⁵⁷⁸^ORCID,Gibson Ronald L.⁹,Cutting Garry R.³^ORCID,Durie Peter R.,Wright Fred A.¹⁰¹¹^ORCID,Zhou Yi-Hui²¹²^ORCID,Blackman Scott M.³¹³^ORCID,O’Neal Wanda K.¹¹⁴^ORCID,Ling Simon C.¹⁵,Knowles Michael R.¹^ORCID

Affiliation:

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

2. Bioinformatics Research Center, Departments of Statistics and Biological Science, North Carolina State University, Raleigh, North Carolina, USA

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

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

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

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

7. Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA

8. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

9. Department of Pediatrics, Division of Pulmonary & Respiratory Diseases, Center for Respiratory Biology and Therapeutics, Seattle Children’s Research Institute, Seattle, Washington, USA

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

11. Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA

12. Departments of Statistics and Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA

13. Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

14. Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

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

Abstract

Background and Aims: It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. Approach and Results: Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (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 of common/rare SNPs; (4) transcriptome-wide association; 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. A genome-wide association study 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. The transcriptome-wide association 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: These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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