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Editors Selection IGR 12-1

Genetics: Gene encoding in XFG

Comment by Wallace Alward 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 • Rand Allingham •

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Exfoliation syndrome (XFS) has always been a difficult disease to study genetically, because it clusters in populations more than in families. A seminal paper by Thorleifsson et al. (890) identified the LOXL1 gene as conferring susceptibility to XFS in Scandinavia. LOXL1 (lyslyl oxidase like protein 1) is a member of a family of proteins that are involved in the formation of elastin polymers and is expressed in many ocular tissues. The authors used single nucleotide polymorphism (SNP) chips with 304,250 SNPs to study 195 glaucoma patients and 14,475 control individuals in Iceland. They found strong signals on chromosome 15q24. Thorleifsson et al. recognized that the signal came exclusively from the 75 patients who had exfoliation glaucoma. They subsequently looked at 55 patients who had exfoliation without glaucoma and confirmed that the LOXL1 gene conferred risk for the development of XFS. These findings were replicated in 199 exfoliation cases and 198 controls from Sweden. When the two populations were combined the significance of this association of LOXL1 with XFS yielded a staggering p-value of 1.0 x 10^-27.

The discovery of LOXL1 is extremely important

Individuals with the highest-risk haplotypes of two SNPs in LOXL1 had a 700-fold higher risk of having XFS than those individuals carrying the lowest-risk haplotype. The authors state that "If the risk of the two higher risk haplotypes, (G,G) and (T,G), could be brought down to that of the (G,A), it would eliminate more than 99% of the XFG cases" (99% attributable risk). The discovery of LOXL1 is extremely important. It will be fascinating to see how it plays out in other populations around the world. It is important to note that the high-risk alleles of LOXL1 are common in the control subjects suggesting the presence of other modifying genes that may also be important in the pathophysiology of exfoliation glaucoma.

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