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Editors Selection IGR 15-4

Genetics: Gene encoding in XFG

Comment by Rand Allingham on:

19653 Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma, Thorleifsson G; Magnusson KP; Sulem P et al., Science, 2007; 317: 1397-1400

See also comment(s) by Rosario Hernandez • Wallace Alward •

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Exfoliation syndrome (XFS, AKA pseudoexfoliation syndrome) is a common ocular syndrome found worldwide. Exfoliation glaucoma (XFG) is the most common secondary form of open-angle glaucoma. The landmark paper by Thorleifsson et al. (890) identified two non-synonymous SNPs of the gene lysyl oxidase like protein 1 (LOXL1) that form the major genetic component for XFS and related glaucoma. These coding variants for LOXL1 are common in the Icelandic and Swedish study populations and account for virtually all of the genetic architecture of XFS and glaucoma in them. It remains to be determined what role LOXL1 plays in other populations around the globe.

Two non-synonymous SNPs of the gene lysyl oxidase like protein 1 (LOXL1) that form the major genetic component for XFS and related glaucoma were identified

Additionally, the contribution of environmental and other genetic factors in the development of the exfoliation process if of great interest. The investigators explored the question of whether POAG shares genetic influences with XFS. Interestingly, variants of LOXL1 played only a marginally significant role in POAG in the Icelandic population (p < 0.04) and were not significantly associated with POAG in the Swedish population. Therefore, exfoliation glaucoma and POAG appear to be genetically discrete forms of glaucoma. In a broader sense, this study demonstrates the power of high throughput SNP-based genome-wide association (GWA) studies for complex disorders. Where traditional family-based genetic linkage studies have led the wave of genetic discovery for rarer Mendelian disorders (e.g., retinitis pigmentosa, nanophthalmus, congenital glaucoma), GWA studies have been increasingly successful for analysis of common complex inherited disorders such as age-related macular degeneration, myocardial infarction, and the identification of major loci for type-2 diabetes. An interesting example of this dichotomy is the genetic linkage analysis of XFS by Lemmelä and co-workers, where a genetic marker near the LOXL1 chromosomal locus produced only minimal evidence for linkage despite a well-designed and executed genetic linkage study of a large Finnish pedigree.

See also the companion review of the paper by Lemmelä et al

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