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• W4281928366 abstract "Cystic fibrosis (CF) is a multi-organ genetic disease with a European prevalence of ∼0.7 per 10,000 people.1Farrell P.M. J Cyst Fibros. 2008; 7: 450-453Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar CF is associated with a decreased life expectancy, primarily related to progressive pulmonary failure.2Flass T. Narkewicz M.R. J Cyst Fibros. 2013; 12: 116-124Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Approximately 5% of people with CF develop a severe hepatic phenotype that comprises cirrhosis, portal hypertension, splenomegaly, and hypersplenism and can lead to variceal bleeding, ascites, hepatopulmonary syndrome, or liver failure. In people with CF, cirrhosis with portal hypertension is usually diagnosed in the first 2 decades of life, with a reported peak incidence at ∼10 years of age, and is associated with an increased mortality risk at younger age.2Flass T. Narkewicz M.R. J Cyst Fibros. 2013; 12: 116-124Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar,3Pals F.H. et al.J Cyst Fibros. 2019; 18: 385-389Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein gene, causing a reduced or absent protein function. More than 2000 CFTR mutations have been identified that to varying degrees negatively influence protein function and phenotype severity.4Clinical and Functional Translation of CFTR (CFTR2).https://cftr2.orgGoogle Scholar A widely accepted method to classify CFTR mutations is based on their consequence on intracellular CFTR endocytic trafficking.5Ameen N. et al.J Cyst Fibros. 2007; 6: 1-14Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Class I mutations include nonsense and splice site mutations, in which no functional CFTR protein is translated. Class II mutations impair intracellular CFTR protein folding. Class III mutations are characterized by impaired gating function of the transport protein, and class IV by decreased conductance. Finally, class V mutations result in the production of functional CFTR protein but in insufficient quantities.6de Boeck K. Amaral M.D. Lancet Respir Med. 2016; 4: 662-674Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar Class I to III mutations are generally associated with more severe phenotypes characterized by declining pulmonary function and exocrine pancreatic insufficiency. Classes IV and V have been associated with a relatively mild phenotype.7Zielenski J. Tsui L.-C. Annu Rev Genet. 1995; 29: 777-807Crossref PubMed Scopus (518) Google Scholar In Europe, ∼85% of the people with CF carry the CFTR F508del mutation, a class II mutation, on at least 1 allele. Around 60% of F508del carriers are homozygous (F508del/F508del), and around 40% are compound heterozygotes, in which a different disease-causing CFTR mutation accompanies 1 F508del mutation on the other allele (F508del/other).7Zielenski J. Tsui L.-C. Annu Rev Genet. 1995; 29: 777-807Crossref PubMed Scopus (518) Google Scholar The relationship between specific CFTR gene mutations and the prevalence of cirrhosis and portal hypertension in people with CF and their mortality risk is unknown. In people with CF who develop clinically significant cirrhosis with portal hypertension, the homozygous F508del mutation is more prevalent compared with people with CF without this severe hepatic phenotype.3Pals F.H. et al.J Cyst Fibros. 2019; 18: 385-389Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,8Boëlle P.Y. et al.Hepatology. 2019; 69: 1648-1656Crossref PubMed Scopus (61) Google Scholar Data on the effects and contribution of more rare CFTR mutations on the severe hepatic phenotype are lacking owing to the relatively low number of patients with those CFTR mutations. The European Cystic Fibrosis Society Patient Registry (ECFSPR) collects yearly data on ∼50,000 European people with CF, including information on CFTR mutations and clinical and biochemical characteristics. Because of the large number of patients included, the registry provides the unique opportunity to study the genotype-phenotype relationship in a rare patient population: people with CF harboring a compound heterozygous mutation. Compound heterozygosity is defined in this study as 1 F508del mutation and 1 other disease-causing mutation, classified by severity. To assess the contribution of these rarer CFTR mutations on severe hepatic phenotype, we collected registry data regarding CFTR mutations, reported liver disease, and mortality of patients harboring at least 1 F508del mutation and 1 other disease-causing mutation. We performed a retrospective analysis of ECFSPR patient data collected from 2008 to 2016. We included data from 17,947 compound heterozygous people with CF. We identified 544 patients (3%) with clinically significant cirrhosis with portal hypertension (CFCPH) in this patient group. We were able to classify the second mutation of 438 patients (∼80%) according to the CFTR protein defect class of their second mutation (Supplementary Data). People with CF harboring a second mutation, which we could not classify, were excluded. The prevalence of CFCPH in compound heterozygous people with CF corresponded with the functional CFTR protein defect class of the second mutation in a stepwise fashion from 5.2% in class I to 0.3% in class V (Figure 1). Subsequently, we assessed the mortality rate during the 8-year study observation window. The mortality rate in the F508del compound heterozygous CFCPH patients was more than 2-fold higher than in the F508del compound heterozygous people with CF without this severe hepatic phenotype (10% vs 4%, respectively; P < .05). This observation underlines the significantly increased mortality risk of CFCPH. When compound heterozygous patients developed CFCPH, the observed mortality rate ranged from 8% to 15%. However, there was no significant association between the severity of the mutation (ie, second mutation class) and the observed mortality risk. We then compared F508del compound heterozygotes and F508del homozygotes with CFCPH. We found similar mortality rates in the 2 groups (10% vs 12%, respectively; P > .05). Our results show that the risk of developing CFCPH in F508del compound heterozygous people with CF is significantly associated with the CFTR functional mutation class of their second CFTR mutation and, subsequently, the severity of CFTR protein dysfunction. The mortality risk of F508del compound heterozygous people who developed CFPCH is almost 2-fold higher than patients without this severe hepatic phenotype. However, once CFCPH had been diagnosed, the subsequent mortality risk was not associated with the mutation class of the second CFTR mutation in F508del compound heterozygotes. The latter indicates that the increased risk of death is mainly determined by the presence of CFCPH and is similar for the different genotypes. This study provides novel insights into the association between the second CFTR gene mutation severity class in F508del compound heterozygous people with CF and the prevalence of CFCPH and subsequent mortality. The characterization of this genotype-phenotype relationship may contribute to an earlier identification of patients at risk and allows for an early and improved prognostication for CFCPH patients. We thank the people with cystic fibrosis and their families for consenting to their data being included in the European Cystic Fibrosis Society Patient Registry (ECFSPR). We thank the centers and individual country representatives, listed in the Supplementary Material, for allowing the use of the data and the ECFSPR for providing access to anonymized patient data. And we thank the C&W de Boer Stichting for generous financial support of these studies. Sanne Suzan Duursma, MSc (Writing – original draft: Lead). Henkjan J. Verkade, Prof Dr (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Supporting; Funding acquisition: Equal; Supervision: Equal; Writing – review & editing: Equal). Frank A.J.A. Bodewes, MD, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Supervision: Lead; Writing – review & editing: Lead). Download .pdf (.28 MB) Help with pdf files Supplemental Table Download .pdf (.13 MB) Help with pdf files Contributors ECFSPR" @default.
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• W4281928366 date "2022-10-01" @default.
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• W4281928366 title "Cirrhosis and Portal Hypertension in Compound Heterozygous People With Cystic Fibrosis Harboring One F508del CFTR Gene Mutation" @default.
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• W4281928366 doi "https://doi.org/10.1053/j.gastro.2022.06.019" @default.
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