title: Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Department of Ophthalmology, Mass Eye and Ear, Boston, MA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Loomis
authors.affiliation: Genentech Inc., San Francisco, CA, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Yaspan
authors.affiliation: Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Bailey
authors.affiliation: Department of Ophthalmology and Hamilton Glaucoma Center, University of California at San Diego, San Diego, CA, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Weinreb
authors.affiliation: Bascom Palmer Eye Institute and Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Lichter
authors.affiliation: Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Budenz
authors.affiliation: 1] Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA [2] Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, WV, USA.
authors.forename: T
authors.initials: T
authors.lastname: Realini
authors.affiliation: Eye Doctors of Washington, Chevy Chase, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gaasterland
authors.affiliation: Scripps Genome Center, University of California at San Diego, San Diego, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gaasterland
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, MD, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Friedman
authors.affiliation: Essentia Institute of Rural Health, Duluth, MN, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Moroi
authors.affiliation: Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Olson
authors.affiliation: Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Schuman
authors.affiliation: Department of Ophthalmology, Stanford University, Palo Alto, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Vollrath
authors.affiliation: Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wollstein
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, MD, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Zack
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Brilliant
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Sit
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Christen
authors.affiliation: Departments of Ophthalmology and Anatomy/Cell Biology, University of Iowa, College of Medicine, Iowa City, IA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fingert
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Forman
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Department of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Department of Ophthalmology and Hamilton Glaucoma Center, University of California at San Diego, San Diego, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Allingham
authors.affiliation: Bascom Palmer Eye Institute and Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Richards
authors.affiliation: 1] Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA [2] Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Hauser
authors.affiliation: Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Ophthalmology, Mass Eye and Ear, Boston, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Wiggs
authors.affiliation: 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Mass Eye and Ear, Boston, MA, USA.
authors.forename: L R
authors.identifier: 0000000258353496
authors.initials: LR
authors.lastname: Pasquale
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D051242:Caveolin 1 / Q000235:genetics; D034285:Dynamin II; D034281:Dynamins / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C000588596:EDNRB protein, human; C578133:GNB2 protein, human; C506929:ITPR3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D019204:GTP-Binding Proteins; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins