Abstract | RATIONALE: OBJECTIVES: To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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%). CONCLUSIONS: 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.
|
Authors | Joseph M Collaco, Scott M Blackman, Karen S Raraigh, Harriet Corvol, Johanna M Rommens, Rhonda G Pace, Pierre-Yves Boelle, John McGready, Patrick R Sosnay, Lisa J Strug, Michael R Knowles, Garry R Cutting |
Journal | American journal of respiratory and critical care medicine
(Am J Respir Crit Care Med)
Vol. 194
Issue 11
Pg. 1375-1382
(12 01 2016)
ISSN: 1535-4970 [Electronic] United States |
PMID | 27258095
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Biomarkers
- Chlorides
- Cystic Fibrosis Transmembrane Conductance Regulator
|
Topics |
- Adult
- Biomarkers
(metabolism)
- Chlorides
(metabolism)
- Cystic Fibrosis
(metabolism)
- Cystic Fibrosis Transmembrane Conductance Regulator
(metabolism)
- Female
- Humans
- Male
- Sweat
(metabolism)
- Young Adult
|