title: Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness.
abstract: OBJECTIVE
  One approach to identify genes that contribute to common complex ocular disorders such as primary open angle glaucoma (POAG) is to study the genetic determinates of endophenotypes that are defined by underlying pre-disposing heritable quantitative traits such as central corneal thickness (CCT). Collagen VIII is a major component of Descemet's membrane and studies in mice have indicated that targeted inactivation of the genes encoding the collagen type 8 alpha1 (Col8a1) and collagen type 8 alpha2 (Col8a2) subunits (COL8A1 and COL8A2) results in thinning of the corneal stroma and of Descemet's membrane. The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients.
  
  
  METHODS
  100 Caucasian POAG patients were enrolled in this study. The entire COL8A1 and COL8A2 coding sequence was determined in 8 patients with CCT<513 µm (one standard deviation (36 microns) below the mean (550 microns) and 8 patients with CCT>586 µm (one standard deviation above the mean). Selected COL8A2 exons containing variants of interest were sequenced in the full POAG cohort. Association and quantitative trait analyses were performed.
  
  
  RESULTS
  Three patients with CCT less than 513 µm and advanced POAG were found to have missense changes in COL8A2; two patients had a previously identified mutation, R155Q and one had a novel change, P678L (p=0.0035, Fisher's exact test). Missense changes were not found in any of the patients with CCT>513 µm and missense changes in the COL8A1 gene were not found in any patient. One common COL8A2 SNP, rs274754 was also statistically associated with CCT (p=0.018).
  
  
  CONCLUSIONS
  In this study we have identified COL8A2 missense changes in a group of Caucasian patients with very thin CCT and advanced POAG. These results suggest that DNA sequence variants in the COL8A2 gene may be associated with thin corneas in some glaucoma patients. Further study of COL8A2 variants in other patient populations, especially those with thinner CCT such as African-Americans would provide further support for a role of COL8A2 in corneal thickness and in glaucoma.
authors.affiliation: Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: T
authors.initials: T
authors.lastname: Desronvil
authors.forename: D
authors.initials: D
authors.lastname: Logan-Wyatt
authors.forename: W
authors.initials: W
authors.lastname: Abdrabou
authors.forename: M
authors.initials: M
authors.lastname: Triana
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Taheri
authors.forename: E
authors.initials: E
authors.lastname: Del Bono
authors.forename: L R
authors.initials: LR
authors.lastname: Pasquale
authors.forename: M
authors.initials: M
authors.lastname: Olivier
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: B J
authors.initials: BJ
authors.lastname: Fan
authors.forename: J L
authors.initials: JL
authors.lastname: Wiggs
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D024102:Collagen Type VIII / Q000737:chemistry / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D003315:Cornea / Q000473:pathology*; D019143:Evolution, Molecular; D005260:Female; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017434:Protein Structure, Tertiary; D040641:Quantitative Trait Loci / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: C443712:COL8A2 protein, human; D024102:Collagen Type VIII