Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

Abstract

Aims: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG.

Methods: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG.

Results: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only.

Discussion: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Figure 1

Paracentral and peripheral VF loss definitions. Representative VF pattern deviation plot used for defining the type of VF loss. The box with a dashed line indicates the superior paracentral region. The boxes with solid lines represent the superior nasal step and temporal wedge regions, as well as the inferior Bjerrum region, which are all peripheral regions. For a case to be defined as having early paracentral loss, VF loss in the superior or inferior paracentral zones had to be present; in the GLAUGEN data set, VF loss in other peripheral zones were allowed, whereas in the NEIGHBOR data set, VF loss in other peripheral zones were not allowed. For a case to be defined as having peripheral loss, VF loss in the superior and/or inferior nasal step, temporal wedge, or Bjerrum regions had to be present, with no loss in the paracentral regions.

Figure 2

Vascular tone pathway. This pathway was custom-generated by using sources from the Kyoto Encyclopedia of Genes and Genomes online database and other academic sources,^, as well as a recent review of the GWAS findings for blood pressure. Proteins coded by genes included in the analysis are in grey. Substrates and reaction products are in green. Overall, the vascular tone pathway was not significantly associated with POAG permuted P=0.87. In exploratory analyses, of the eight proteins of genes with permuted P-values <0.001, seven are indicated with red squares, with the remaining being the HFE gene, which was included in the analysis as part of genes identified from a review of known blood pressure SNPs.