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In clinical routine the diagnosis of cystic fibrosis CF is still challenging regardless of international consensus on diagnosis guidelines and tests For decades the classical Gibson and Cooke test measuring sweat chloride concentration has been a keystone yet it may provide normal or equivocal results As of now despite the combination of sweat testing CFTR genotyping and CFTR functional testing a small fraction 1-2 of inconclusive diagnoses are reported and justifies the search for new CF biomarkers More importantly in the context of precision medicine with a view to early diagnosis better prognosis appropriate clinical follow-up and new therapeutic development discovering companion biomarkers of CF severity and phenotypic rescue are of utmost interest To date previous sweat proteomic studies have already documented disease-specific variations of sweat proteins e g in schizophrenia and tuberculosis In the current study sweat samples from 28 healthy control subjects and 14 patients with CF were analyzed by nanoUHPLC-Q-Orbitrap-based shotgun proteomics to look for CF-associated changes in sweat protein composition and abundance A total of 1057 proteins were identified and quantified at an individual level by a shotgun label-free approach Notwithstanding similar proteome composition enrichment and functional annotations control and CF samples featured distinct quantitative proteome profiles significantly correlated with CF accounting for the respective inter-individual variabilities of control and CF sweat All in all i 402 sweat proteins were differentially abundant between controls and patients with CF ii 68 proteins varied in abundance between F508del homozygous patients and patients with another genotype iii 71 proteins were differentially abundant according to the pancreatic function and iv 54 proteins changed in abundance depending on the lung function The functional annotation of pathophysiological biomarkers highlighted eccrine gland cell perturbations in i protein biosynthesis and trafficking ii CFTR proteostasis and membrane stability and iii cell-cell adherence membrane integrity and cytoskeleton crosstalk Cytoskeleton-related biomarkers were of utmost interest because of the consistency between variations observed here in CF sweat and variations previously documented in other CF tissues From a clinical stance nine candidate biomarkers of CF diagnosis CUTA ARG1 EZR AGA FLNA MAN1A1 MIA3 LFNG SIAE and seven candidate biomarkers of CF severity ARG1 GPT MDH2 EML4 F508del homozygous MGAT1 pancreatic insufficiency IGJ TOLLIP lung function impairment were deemed suitable for further verification

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Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development...