title: SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients.
abstract: OBJECTIVE
  To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).
  
  
  METHODS
  A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 normal tension glaucoma, NTG) and 281 unrelated control subjects were recruited. All coding exons and splicing junctions in MYOC and OPTN were screened for sequence alterations. Common polymorphisms in APOE were genotyped. Single genes were investigated by univariate and haplotype analysis, and gene-gene interactions by logistic regression and stratified analysis. Multiple comparisons were corrected by the Bonferroni method. Bioinformatics analysis was performed to assess the conservation of mutation sites across species and to predict putative motifs and secondary structures in mutated proteins.
  
  
  RESULTS
  Disease-causing mutations in MYOC and OPTN were identified in 1.75% and 1% of POAG patients, respectively. Most of these mutations were highly conserved across species, many predicted to create new motifs or change protein secondary structures. No individual MYOC polymorphisms significantly contributed to HTG or NTG. A haplotype containing the minor allele of the MYOC IVS2+35A>G increased NTG risk (p=0.0001). Three OPTN polymorphisms, T34T, IVS5+38T>G, and IVS8-53T>C increased NTG risk (p<0.0008), while IVS5+38T>G increased HTG risk (p=0.0006). One haplotype that contains the minor alleles of 3 OPTN polymorphisms, T34T, IVS5+38T>G, and IVS7+24G>A, increased NTG risk (p=0.0002). APOE epsilon4 carriers had a decreased NTG risk (p=0.007). Possible gene-gene interactions were found between MYOC, OPTN, and APOE.
  
  
  CONCLUSIONS
  Disease-causing mutations in MYOC and OPTN accounted for only a small proportion of Chinese POAG patients. Common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG, indicating a polygenic etiology.
authors.affiliation: Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China. bjfan@cuhk.edu.hk
authors.forename: Bao Jian
authors.initials: BJ
authors.lastname: Fan
authors.forename: Dan Yi
authors.initials: DY
authors.lastname: Wang
authors.forename: Dorothy Shu Ping
authors.initials: DS
authors.lastname: Fan
authors.forename: Pancy Oi Sin
authors.initials: PO
authors.lastname: Tam
authors.forename: Dennis Shun Chiu
authors.initials: DS
authors.lastname: Lam
authors.forename: Clement Chuu Yang
authors.initials: CC
authors.lastname: Tham
authors.forename: Ching Yan
authors.initials: CY
authors.lastname: Lam
authors.forename: Tung Ching
authors.initials: TC
authors.lastname: Lau
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA; D035582:Transcription Factor TFIIIA / Q000235:genetics*; D000099179:Myocilin
chemical_list: D001057:Apolipoproteins E; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D035582:Transcription Factor TFIIIA; D000099179:Myocilin; C409460:OPTN protein, human