TY - JOUR
T1 - Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression
AU - Muilwijk, Danya
AU - de Poel, Eyleen
AU - van Mourik, Peter
AU - Suen, Sylvia W F
AU - Vonk, Annelotte M
AU - Brunsveld, Jesse E
AU - Kruisselbrink, Evelien
AU - Oppelaar, Hugo
AU - Hagemeijer, Marne C
AU - Berkers, Gitte
AU - de Winter-de Groot, Karin M
AU - Heida-Michel, Sabine
AU - Jans, Stephan R
AU - van Panhuis, Hannah
AU - van der Eerden, Menno M
AU - van der Meer, Renske
AU - Roukema, Jolt
AU - Dompeling, Edward
AU - Weersink, Els J M
AU - Koppelman, Gerard H
AU - Vries, Robert
AU - Zomer-van Ommen, Domenique D
AU - Eijkemans, Marinus J C
AU - van der Ent, Cornelis K
AU - Beekman, Jeffrey M
N1 - Copyright ©The authors 2022. For reproduction rights and permissions contact [email protected].
PY - 2022
Y1 - 2022
N2 - RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC.CONCLUSION: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.
AB - RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC.CONCLUSION: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.
U2 - 10.1183/13993003.00508-2021
DO - 10.1183/13993003.00508-2021
M3 - Article
C2 - 35086832
SN - 0903-1936
VL - 60
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
M1 - 2100508
ER -