Distribution of WDR36 DNA Sequence Variants in Primary Open Angle Glaucoma Patients

Abstract

Purpose: : Recently DNA sequence variants in WDR36 have been identified in patients with high and low tension glaucoma (Monemi et al., Hum Molec Genetics, 14:725–733). WDR36 is a member of the WD40 repeat protein family and may be involved in T cell activation. Recently, T–cell mediated responses have been hypothesized to participate in glaucoma associated optic nerve degeneration. The purpose of this study is to determine the distribution of WDR36 DNA sequence variants in a well–studied cohort of primary open angle glaucoma (POAG) patients from the United States.

Methods: : After PCR amplification all of the 23 coding exons and flanking introns of the WDR36 gene were screened by direct genomic sequencing in 118 probands from families with at least two members affected by primary open angle glaucoma and 108 control individuals. POAG was defined as age of onset > 35 with intraocular pressure greater than 22 mm Hg in both eyes without medications or 19 mm Hg on two or more medications, glaucomatous optic nerve damage in both eyes, and visual field loss in at least one eye. Level I patients met all three of the criteria, while Level II patients met 2 of the 3 criteria.

Results: : 32 WDR36 sequence variants were found in this population of POAG patients. Nonsynonymous SNPs (including those previously described as ‘disease–causing’ and ‘disease–susceptibility’ were found in 17% of POAG patients and 4% of controls. Although the distribution of WDR36 variants in the pedigrees did not show consistent segregation with the disease, the WDR36 sequence variants were found more frequently in Level I patients with more severe disease, than Level II patients. In particular, the Level I patients with WDR36 gene defects had more severe optic nerve defects.

Conclusions: : The results of our study suggest that abnormalities in WDR36 alone are not sufficient to cause primary open angle glaucoma. The association of WDR36 sequence variants with more severe disease in affected individuals suggests that defects in the WDR36 gene can contribute to POAG, and that WDR36 may be a glaucoma modifier gene. The higher frequence of WDR36 sequence variants in patients with more severe optic nerve disease may indicate that the WDR36 protein contributes to glaucoma by modifying optic nerve degeneration; however, further work defining the role of the protein in POAG is necessary before this conclusion can be reached.

Keywords: candidate gene analysis • gene modifiers • optic disc