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Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4570-81. doi: 10.1167/iovs.15-16736.

Gene Expression-Based Predictive Models of Graft Versus Host Disease-Associated Dry Eye.

Author information

1
Institute of Applied Ophthalmobiology (IOBA), University of Valladolid, Valladolid, Spain.
2
Institute of Applied Ophthalmobiology (IOBA), University of Valladolid, Valladolid, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain.
3
Hematology Service, University Hospital, Instituto Biosanitario de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
4
Allergan, Inc., Irvine, California, United States.

Abstract

PURPOSE:

To develop a predictive model based on inflammatory gene mRNA expression in conjunctival cells of graft versus host disease (GvHD)-associated dry eye (DE) patients, as well as to find meaningful correlations between gene signals and clinical signs.

METHODS:

Twenty GvHD-DE patients and 14 healthy controls were recruited. Patients discontinued medications for 1 week before examination. Dry eye-related symptoms and signs were recorded, and conjunctival epithelial cells were collected by impression cytology after spending 20 minutes under standard conditions within a Controlled Environmental Research Laboratory. Gene expression of inflammatory molecules was determined by polymerase chain reaction, and the results were correlated with clinical signs. Shrinkage discriminant analysis, support vector machine, and k-nearest neighbor classifier methods were used to develop predictive models that were validated considering accuracy, calibration, and discriminant capability.

RESULTS:

Out of the 84 genes analyzed, 34 showed significant differences in expression. IL-6, IL-9, CCL24, CCL18, IL-10, IFN-γ, and CCL2 were highly increased (>6-fold); 26 genes were moderately upregulated (2- to 6-fold), whereas EGFR was downregulated (2.63 fold) in GvHD-DE samples. A panel based on EGFR, IL-6, IL-9, and NAMPT had an area under the receiver operating characteristic curve of 0.994, a sensitivity of 100%, and a specificity of 92.9%. EGFR expression correlated negatively with ocular surface damage markers, while IL-6, IL-9, and NAMPT correlated positively with these tests.

CONCLUSIONS:

EGFR, IL-6, IL-9, and NAMPT have the greatest potential as diagnostic biomarkers, with excellent sensitivity, specificity, and clinical relevance to the ocular surface status of GvHD.

PMID:
26200497
DOI:
10.1167/iovs.15-16736
[Indexed for MEDLINE]

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