Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
Purpose
To develop and validate an associative model using pupillography that
best discriminates those with and without glaucoma.
Design
A prospective case-control study.
Methods
148 patients with glaucoma (mean age 67±11) and 71 controls
(mean age 60±10) were enrolled in a clinical setting. This prototype
pupillometer is designed to record and analyze pupillary responses at
multiple, controlled stimulus intensities, while using varied stimulus
patterns and colors. We evaluated three approaches: 1) comparing the
responses between the two eyes, 2) comparing responses to stimuli between
the superonasal and inferonasal fields within each eye, and 3) calculating
the absolute pupil response of each individual eye. Associative models were
developed using stepwise regression or forward selection with Akaike
information criterion and validated with 5-fold cross validation. We
assessed the associative model using sensitivity, specificity and the area
under the receiver operating characteristic curve (AUROC).
Results
Persons with glaucoma had a more asymmetric pupil response between
the two eyes (p<0.001), between superonasal and
inferonasal visual field within the same eye
(p=0.014), and also had a smaller amplitude, slower
velocity and longer latency of pupil response compared to controls (all
p<0.001). A model including age and these three
components resulted in an AUROC of 0.87 (95% CI 0.83 to 0.92) with
80% sensitivity and specificity in detecting glaucoma. This result
remained robust after cross-validation.
Conclusions
Using pupillography, we were able to discriminate persons with
glaucoma from those with normal eye exams. With refinement, pupil testing
may provide a simple approach for glaucoma screening.
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