Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Abstract

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.

Recent advances in risk factors associated with ocular exfoliation syndrome

“…It is believed that altered elastin metabolism in extracellular matrix due to protective effect of identified variant could improve cell‐matrix adhesion and possibly slow down the exfoliative process (Aung et al. , ).…”

“…Besides CACNA1A and LOXL1, other newly identified genes also have functional roles that might be involved in the pathobiology of XFS (Aung et al. ; Schlötzer‐Schrehardt ).…”

What have we learned about exfoliation syndrome since its discovery by John Lindberg 100 years ago?

“…The authors suggest that the protective effect may be via stabilisation of extracellular matrix from increased elastin and fibrillin-1 deposition. In the same paper, five new loci that serve as genetic risk factors were identified and suggest new biological pathways for pathogenesis 61. The loci include POMP, TMEM136, AGPAT1, RBMS3 and SEMA6A 61.…”

“…CACNA1A was discovered as the second locus associated with susceptibility to XFS 60. A recent study uncovered a rare variant in LOXL1, p.Tyr407Phe, that interestingly strongly protects against XFS 61. The authors suggest that the protective effect may be via stabilisation of extracellular matrix from increased elastin and fibrillin-1 deposition.…”

“…In the same paper, five new loci that serve as genetic risk factors were identified and suggest new biological pathways for pathogenesis 61. The loci include POMP, TMEM136, AGPAT1, RBMS3 and SEMA6A 61. Potential pathophysiological pathways include effects on ubiquitin-conjugating enzymes (POMP), vascular endothelia (TMEM136), omega-6 polyunsaturated fatty acid levels (AGPAT1) and other yet to be discovered biological pathways.…”