https://pubmed.ncbi.nlm.nih.gov/38536042/ cystic fibrosis

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

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

Jaclyn R Stonebraker 1, Rhonda G Pace 1, Paul J Gallins 2, Hong Dang 1, Melis A Aksit 3, Anna V Faino 4, William W Gordon 5, Sonya MacParland 6, Michael J Bamshad 5 7 8, Ronald L Gibson 9, Garry R Cutting 3, Peter R Durie, Fred A Wright 10 11, Yi-Hui Zhou 2 10, Scott M Blackman 3 12, Wanda K O'Neal 1, Simon C Ling 13, Michael R Knowles 1
Affiliations expand
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 (pwCF). We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms.

Approach and 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: 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.