Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis.
BACKGROUND
Cystic Fibrosis (CF) is caused by ∼1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl(-)) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases.


RESULTS
To further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl(-) secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n=51), individuals with clinical CF suspicion (n=49) and age-matched non-CF controls (n=18). Conclusive measurements were obtained for 96% of cases. Patients with "Classic CF", presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl(-) secretion (<5%). Individuals with milder CF disease presented residual CFTR-mediated Cl(-) secretion (10-57%) and non-CF controls show CFTR-mediated Cl(-) secretion ≥ 30-35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in "CF suspicion" individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl(-) secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups.


CONCLUSIONS
Determination of CFTR-mediated Cl(-) secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-)clinical trials of CFTR-modulator therapies.
BioFIG - Centre for Biodiversity, Functional and Integrative Genomics, Faculty of Sciences, University of Lisboa, Lisboa, Portugal.
Marisa
M
Sousa
Maria F
MF
Servidoni
Adriana M
AM
Vinagre
Anabela S
AS
Ramalho
Luciana C
LC
Bonadia
Verónica
V
Felício
Maria A
MA
Ribeiro
Inna
I
Uliyakina
Fernando A
FA
Marson
Arthur
A
Kmit
Silvia R
SR
Cardoso
José D
JD
Ribeiro
Carmen S
CS
Bertuzzo
Lisete
L
Sousa
Karl
K
Kunzelmann
Antônio F
AF
Ribeiro
Margarida D
MD
Amaral
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D011379:Prognosis; D012007:Rectum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016896:Treatment Outcome
D015415:Biomarkers; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D002217:Carbachol; D015056:1-Methyl-3-isobutylxanthine