Editors Selection IGR 12-3

Genetics: Genetics of PXFG

Richard Lee

Comment by Richard Lee on:

26639 Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome, Krumbiegel M; Pasutto F; Schlotzer-Schrehardt U et al., European Journal of Human Genetics, 2010;

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Pseudoexfoliation glaucoma (PXFG)had long been suspected to have agenetic link, which was confirmedrecently with the identification of singlenucleotide polymorphisms (SNP) inthe lysyl oxidase-like1 (LOXL1) whichwere highly sensitive for PXFG butnot very specific. Thus, environmentalco-factors or other genes, either aloneor in conjunction with LOXL1, are permissive for the PXFG phenotype.PXFG is diagnosed by the slit lamp observation of pseudoexfoliationmaterial (PXFM) in the anterior segment of the eye. Not all eyeswhich have PXFM have glaucoma, but these are nonetheless pseudoexfoliation (PXF) eyes at significantly increased risk for developing glaucoma. PXFM has been shown by Barbara Streeten, Gottfried Naumann and others by electron microscopy to have an orderly, fibrillar, and amyloid-like appearance. Thus, attention has been drawn to apolipoprotein E (APOE), which is an amyloid-associated protein, as a co-factor in PXFG.

Environmental co-factors or other genes, either alone or in conjunction with LOXL1, are permissive for the PXFG phenotype

Krumbiegel et al. (1271) prospectively genotyped a large cohort of PXFG, PXF, and normal patients from an Italian and a German cohort for SNPs associated with the APOE gene. No significant differences in the APOE allele frequencies were observed between normal and PXFG and PXF patients. In addition, the authors compared the allele frequencies of the APOE polymorphisms to carriers and non-carriersof the LOXL1 polymorphism associated with pseudoexfoliation and also found no difference. Thus, the authors found no genetic correlation between APOE and pseudoexfoliation. In addition, when they looked at patients who carried the LOXL1 SNPs associated with LOXL1, the lack of a difference suggests APOE also does not have any effect between the LOXL1 gene and pseudoexfoliation. The allele differences for the three major isoforms of APOE were similar between the Italian and the German population. This suggests that the study population did not have any inherent genetic bias for study of the APOE gene relative to pseudoexfoliation.

The authors studied APOE as a genetic risk factor for pseudoexfoliation because APOE plays a role in Alzheimers Disease, which is caused by amyloid proteins which are similar to those structurally observed in PXFM. However, the authors found no genetic association between APOE and pseudoexfoliation. This result adds to the number of other genes, including elastin and other genes associated with PXFM, which have not been found to be associated with PXF. Thus, genetic associations other than LOXL1 are probably relative weak and may involve disease modifying genes associated with environmental and age-associated changes which create a permissive environment for PXFM formation and PXFG. Optic Disc

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