Association of A COCH Promoter Region Polymorphism With IOP In POAG Patients

Abstract

Purpose: : Our previous genome-wide linkage study of Caucasian primary open angle glaucoma (POAG) identified a locus on 14q11, and fine-mapping of this region has identified a 3.5 Mb region likely to harbor a susceptibility gene. Twelve genes are located in this region and of these, the coagulation factor C homolog (COCH) gene has been shown to have increased expression in human glaucomatous trabecular meshwork (TM) and glaucomatous DBA/2J mice TM. The purpose of this study is to investigate common COCH polymorphisms for association with POAG.

Methods: : Fifteen tag SNPs in the vicinity of COCH, capturing 100% of alleles with mean r-square of 0.95 were genotyped in a MEEI cohort of 539 Caucasian patients with POAG and 336 controls, as well as a SNP (rs3759777) located in the promoter. Three SNPs (rs3759777, rs8015095 and rs1124181) were further genotyped in an independent Caucasian sample set of 341 POAG patients and 180 controls from Duke. SNP association analysis was performed for POAG using the Fisher’s exact test. POAG was defined as vertical cup disc ratio (VCDR) >0.8 with visual field defects consistent with optic nerve defects. Intraocular pressure (IOP) was not part of the case definition although it was recorded and corrected by central corneal thickness.

Results: : All SNPs followed Hardy-Weinberg equilibrium in both cases and controls. Significant association was found between rs8015095 and IOP with the minor allele frequency highest in patients whose IOP corrected for central corneal thickness (CCT) is not higher than 22 mmHg (p=0.038 for the MEEI cohort, 0.021 for the Duke cohort, and 0.0018 for the meta-analysis).

Conclusions: : Previous studies have suggested that Cochlin, the product of the COCH gene accumulates in the TM in response to elevated IOP, and that this may be due to pressure effects on gene expression. rs8015095 is located 500 bp from the COCH transcription start site and about 1500 bp from conserved binding sites for transcription factors FOXO3, FREAC4 and FREAC2. Our results suggest that rs8015095 may influence COCH gene expression or may be in linkage disequilibrium with other variants that could affect promoter efficiency. Further studies of COCH promoter activity in glaucoma patients could define a role for Cochlin in the disease.

Keywords: genetics • transcription factors