A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma.

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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.

Exfoliation syndrome (XFS) is the commonest recognizable cause of open angle glaucoma world-wide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) on 1,484 patients and 1,188 controls from Japan, and followed up the most significant findings on a further 6,901 patients and 20,727 controls from 17 countries across 6 continents. We discovered a significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (Odds ratio [OR] = 1.16, P = 3.36 × 10−11). Although overwhelming association at the LOXL1 locus was confirmed, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on ethnic grouping (In Japanese: ORA-allele= 9.87, P = 2.13 × 10−217; In non-Japanese: ORA-allele= 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 which surpasses genome-wide significance for XFS, and provides insight into the biology and pathogenesis of the disease.

Purpose To establish the antioxidant status of the aqueous humour in glaucoma associated with exfoliation syndrome (XFG) and to compare it to primary open-angle glaucoma (POAG) and cataract patients. Methods Patients were diagnosed with POAG, XFG, or cataract (n ¼ 25 for each group). Total reactive antioxidant potential (TRAP) was measured by chemiluminescence. Ascorbic acid levels and the activities of catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD) were measured spectrophotometrically.Results TRAP value was lower in XFG (28 ± 2 lM Trolox) than in POAG (55 ± 8 lM Trolox; Po0.001). TRAP values in both glaucomas were lower than the cataract value (124±5 lM Trolox; Po0.001). A decrease in ascorbic acid was measured in XFG (230±20 lM) compared with POAG (415±17 lM; Po0.001). Ascorbic acid in both glaucomas was lower than in cataract (720 ± 30 lM; Po0.001). A significant increase in GPx was found in XFG (30 ± 2 U/ml) compared with POAG (16 ± 3 U/ml). GPx activity in both glaucomas was increased when compared with cataracts (6±2 U/ml; Po0.001). A significant increase of 67% in SOD activity was observed in the glaucoma group vs cataract group (27 ± 3 U/ml; Po0.001), but no changes were found between both glaucomas. Conclusions The antioxidant status of the aqueous humour may play a role in the pathophysiology of both glaucomas.