title: Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States.
abstract: OBJECTIVE
  Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender.
  
  
  METHODS
  We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women.
  
  
  RESULTS
  Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01).
  
  
  CONCLUSIONS
  The estrogen SNP pathway was associated with POAG among women.
authors.affiliation: Department of Ophthalmology, Mass Eye & Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA. Louis_Pasquale@meei.harvard.edu
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Loomis
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Jae H
authors.initials: JH
authors.lastname: Kang
authors.forename: Brian L
authors.initials: BL
authors.lastname: Yaspan
authors.forename: Jessica Cooke
authors.initials: JC
authors.lastname: Bailey
authors.forename: Douglas
authors.initials: D
authors.lastname: Gaasterland
authors.forename: Terry
authors.initials: T
authors.lastname: Gaasterland
authors.forename: Richard K
authors.initials: RK
authors.lastname: Lee
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lichter
authors.forename: Donald L
authors.initials: DL
authors.lastname: Budenz
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Tony
authors.initials: T
authors.lastname: Realini
authors.forename: David S
authors.initials: DS
authors.lastname: Friedman
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.forename: Sayoko E
authors.initials: SE
authors.lastname: Moroi
authors.forename: Lana
authors.initials: L
authors.lastname: Olson
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schuman
authors.forename: Kuldev
authors.initials: K
authors.lastname: Singh
authors.forename: Douglas
authors.initials: D
authors.lastname: Vollrath
authors.forename: Gadi
authors.initials: G
authors.lastname: Wollstein
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Murray
authors.initials: M
authors.lastname: Brilliant
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Sit
authors.forename: William G
authors.initials: WG
authors.lastname: Christen
authors.forename: John
authors.initials: J
authors.lastname: Fingert
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Julia E
authors.initials: JE
authors.lastname: Richards
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
mesh_terms: D016022:Case-Control Studies; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics*; D014481:United States
chemical_list: D004967:Estrogens