Caveolin-Soluble Guanylate Cyclase Single Nucleotide Polymorphism Score in Relation to Primary Open Angle Glaucoma in the NEIGHBORHOOD Consortium

Abstract

Purpose: Caveolin is biophysically partitioned with nitric oxide synthase 3 (NOS3) in endothelial cell membranes and serves to modulate NOS3 activity. Soluble guanylate cyclase (sGC) is the intracellular receptor for nitric oxide (NO) produced by NOS3. Binding of NO to sGC results in vasorelaxation. Caveolin 1 /Caveolin 2 (CAV1/CAV2) variants are associated with POAG and the sGC knock out mouse develops open angle glaucoma. Here we analyze the association between a combined CAV1/CAV2 - GUCY1A3/GUCY1B3 single nucleotide polymorphism (SNP) score in association with primary open-angle glaucoma (POAG) overall and POAG stratified by pattern of visual field loss.

Methods: We generated a panel SNP score ranging from 0-4 risk alleles for two loci: the CAV1/CAV2 intergenic rs4236601 and the GUCY1A3/GUCY1B3 intergenic rs11722059. Genotyping data was derived from the Illumina Human 660WQuadv1C BeadChip array among participants in the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). We used logistic regression models of POAG in the overall population and subsequently we analyzed cases with incident paracentral and peripheral visual field (VF) loss. Results from the GLAUGEN study and NEIGHBOR consortium were meta-analyzed with the METAL software package.

Results: 18% of POAG cases in GLAUGEN and 2% of cases in the NEIGHBOR consortium presented with paracentral visual loss. Each at risk allele of the CAV/CAV2_GUCY1A3/GUCY1B3 SNP score was associated with 16% increased risk of POAG overall (OR=1.16 (95% confidence interval (CI): 1.09-1.24); p=1.07E-05) in the combined GLAUGEN-NEIGHBOR dataset after controlling for appropriate covariates. Each at risk allele of the CAV1/CAV2_GUCY1A3/GUCY1B3 SNP score was associated with 42% increased risk of POAG with paracentral VF loss (OR=1.42 (95% CI: 1.21-1.67); p=2.05E-05) and a 13% increase of POAG with peripheral VF loss (OR=1.13 (95% CI: 1.04-1.24); p=5.80E-03) in the combined GLAUGEN-NEIGHBOR dataset after controlling for appropriate covariates.

Conclusions: These data suggest that common variants related to NO signaling are associated with POAG, highlighting a role for nitric oxide signaling in POAG pathogenesis.

Keywords: 539 genetics