Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Cystic Fibrosis (CF) is caused by similar to 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. Methodology/Principal Findings: 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 (= 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/Significance: 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.710TargetScreen2 [EU/FP6/LSH/2005/037365, PIC/IC/83103/2007]FCT (Portugal) [PEstOE/BIA/UI4046/2011, PEstOE/MAT/UI0006/2011, SFRH/BD/35936/2007, SFRH/BD/69180/2010]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Mukoviszidose e.V. (Germany) [S02/10][PTDC/MAT/118335/2010]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)TargetScreen2 [EU/FP6/LSH/2005/037365, PIC/IC/83103/2007]FCT (Portugal) [PEstOE/BIA/UI4046/2011, PEstOE/MAT/UI0006/2011, SFRH/BD/35936/2007, SFRH/BD/69180/2010]CNPq [40.8924/2006/3]Mukoviszidose e.V. (Germany) [S02/10][PTDC/MAT/118335/2010