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

Jaclyn R Stonebraker; Rhonda G Pace; Paul J Gallins; Hong Dang; Melis A Aksit; Anna V Faino; William W Gordon; Sonya MacParland; Michael J Bamshad; Ronald L Gibson; Garry R Cutting; Peter R Durie; Fred A Wright; Yi-Hui Zhou; Scott M Blackman; Wanda K O'Neal; Simon C Ling; Michael R Knowles

doi:10.1097/HEP.0000000000000863

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

Hepatology. 2024 Mar 27. doi: 10.1097/HEP.0000000000000863. Online ahead of print.

Authors

Jaclyn R Stonebraker¹, Rhonda G Pace¹, Paul J Gallins², Hong Dang¹, Melis A Aksit³, Anna V Faino⁴, William W Gordon⁵, Sonya MacParland⁶, Michael J Bamshad^{5

7

8}, Ronald L Gibson⁹, Garry R Cutting³, Peter R Durie, Fred A Wright^{10

11}, Yi-Hui Zhou^{2

12}, Scott M Blackman^{3

13}, Wanda K O'Neal^{1

14}, Simon C Ling¹⁵, Michael R Knowles¹

Affiliations

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.

PMID: 38536042
DOI: 10.1097/HEP.0000000000000863

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.