Variation in CFTR-dependent 'β-sweating' among healthy adults

Area of Science:

• Physiology
• Genetics
• Pharmacology

Background:

• Cystic fibrosis (CF) is a genetic disease caused by reduced activity of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel.
• Small molecule therapies partially restore CFTR function, necessitating accurate methods to assess CFTR activity in vivo.
• Current in vivo CFTR activity measurements vary widely, highlighting the need for reliable benchmarks.

Purpose of the Study:

• To establish a precise benchmark for CFTR activity in healthy control subjects using the sweat rate ratio (β/M).
• To quantify the range of CFTR activity in a healthy population to facilitate comparison with CF patients and treatment responses.

Main Methods:

• Analysis of the β/M sweat rate ratio in 50 healthy adults.
• Repeated measurements (3x) of sweat rates stimulated by cholinergic and β-adrenergic agonists in approximately 50 identified sweat glands per individual.
• Compilation of approximately 20,000 individual sweat gland measurements.

Main Results:

• The study identified an approximately 7-fold range in CFTR activity among healthy adults, from 26% to 187% of the wild-type (WT) average.
• The WT average CFTR activity was normalized to 100% for comparison.
• Significant variation in CFTR activity was observed within the healthy control group.

Conclusions:

• The established β/M ratio benchmark provides a critical reference for evaluating CFTR function in CF patients undergoing treatment.
• Understanding the natural variation in CFTR activity in healthy individuals is essential for interpreting therapeutic efficacy.
• Further investigation into factors contributing to β/M variation in healthy controls is warranted.