Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis.
Expanding the use of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors for the treatment of cystic fibrosis (CF) requires precise and accurate biomarkers. Sweat chloride concentration provides an in vivo assessment of CFTR function, but it is unknown the degree to which CFTR mutations account for sweat chloride variation.



To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself.



A total of 2,639 sweat chloride measurements were obtained in 1,761 twins/siblings from the CF Twin-Sibling Study, French CF Modifier Gene Study, and Canadian Consortium for Genetic Studies. Variance component estimation was performed by nested mixed modeling.



Across the tested CF population as a whole, CFTR gene mutations were found to be the primary determinant of sweat chloride variability (56.1% of variation) with contributions from variation over time (e.g., factors related to testing on different days; 13.8%), environmental factors (e.g., climate, family diet; 13.5%), other residual factors (e.g., test variability; 9.9%), and unique individual factors (e.g., modifier genes, unique exposures; 6.8%) (likelihood ratio test, P < 0.001). Twin analysis suggested that modifier genes did not play a significant role because the heritability estimate was negligible (H2= 0; 95% confidence interval, 0.0-0.35). For an individual with CF, variation in sweat chloride was primarily caused by variation over time (58.1%) with the remainder attributable to residual/random factors (41.9%).



Variation in the CFTR gene is the predominant cause of sweat chloride variation; most of the non-CFTR variation is caused by testing variability and unique environmental factors. If test precision and accuracy can be improved, sweat chloride measurement could be a valuable biomarker for assessing response to therapies directed at mutant CFTR.
1 School of Medicine and.
Joseph M
0000-0002-2581-4372
JM
Collaco
1 School of Medicine and.
Scott M
SM
Blackman
1 School of Medicine and.
Karen S
KS
Raraigh
2 Assistance Publique-Hôpitaux de Paris, Trousseau Hospital, Paris, France.|3 Institut National de la Santé et la Recherche Médicale, Paris, France.
Harriet
H
Corvol
4 The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Johanna M
JM
Rommens
5 Marsico Lung Institute/Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Rhonda G
RG
Pace
3 Institut National de la Santé et la Recherche Médicale, Paris, France.|6 Sorbonne Universités, Université Pierre et Marie Curie, Paris, France; and.|7 Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, Paris, France.
Pierre-Yves
PY
Boelle
8 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
John
J
McGready
1 School of Medicine and.
Patrick R
PR
Sosnay
4 The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Lisa J
LJ
Strug
5 Marsico Lung Institute/Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Michael R
MR
Knowles
1 School of Medicine and.
Garry R
GR
Cutting
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D013542:Sweat / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
biomarker; heritability; ivacaftor; lumacaftor; pilocarpine iontophoresis