AimsVascular 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.MethodsWe 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.ResultsThe 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.DiscussionAlthough 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.
Bibliographical noteFunding Information:
A Horizon Grant to MEEI from Allergan (Irvine, CA, USA) supported the collection of some glaucoma feature data. The Harvard Glaucoma Center of Excellence, a Harvard Department of Ophthalmology Scholar Award, and Margolis fund (Boston, MA) support LRP and JLW. LRP, JER, and JLW are also supported by Research to Prevent Blindness Inc. (New York, NY, USA). The Arthur Ashley Foundation also supports Dr Pasquale. The Glaucoma Research Foundation (San Francisco, CA, USA), American Health Assistance Foundation (Clarksburg, MD, USA), and the Glaucoma Foundation (New York, NY, USA) support YL. EB is supported by NIH Grant R01EY022746. The following National Institutes of Health grants support the maintenance of the NHS and Health Professionals Follow-up, allowing these health professionals to contribute to this analysis: P01 CA87969, CA49449, UM1 CA167552, and HL35464. The following grants from the National Human Genome Research Institute (Bethesda, MD, USA) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), and HG004446 (C Laurie, U Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through Grant HG005259-01 (JLW). In addition, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The National Eye Institute (Bethesda, MD) through ARRA Grants 3R01EY015872-05S1 (JLW) and 3R01EY019126-02S1 (MAH) supported the collection and processing of samples for the NEIGHBOR data set. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, MD) Grants: EY015543 (RRA), EY006827 (DG), HL073389 (E Hauser); EY13315 (MAH); EY09611 (S Hankinson), EY015473 (LRP), EY009149 (PRL), HG004608 (CAM), EY008208 (P Medeiros), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY013178 (JSS), EY010886 (JLW), EY009847 (JLW), EY011008 (L Zangwill), EY144428 (KZ), EY144448 (KZ), EY18660 (KZ), UL1TR000427 (MHB) and U01HG006389 (CAM), P30 EY014104, R01 EY022305, and R21 EY022766.