title: Novel quantitative trait loci for central corneal thickness identified by candidate gene analysis of osteogenesis imperfecta genes.
abstract: Osteogenesis imperfecta (OI) is a rare connective tissue disorder caused by mutations in the type I collagen genes, COL1A1 and COL1A2, and is characterised by low bone mass and bone fragility. In this study, we explored the relationship between type 1 collagen genes and the quantitative trait central corneal thickness (CCT). CCT was measured in a cohort of 28 Australian type I OI patients and mean CCT was found to be significantly lower compared to a normal population (P < 0.001). We then investigated CCT and corneal collagen fibril diameter and density in a mouse model of OI with a col1a2 mutation. Mean CCT was significantly lower in mutant mice (P = 0.002), as was corneal collagen fibril diameter (P = 0.034), whilst collagen fibril density was significantly greater in mutants (P = 0.034). Finally, we conducted a genetic study to determine whether common single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2 are associated with CCT variation in the normal human population. Polymorphism rs2696297 (P = 0.003) in COL1A1 and a three SNP haplotype in COL1A2 (P = 0.007) were all significantly associated with normal CCT variation. These data implicate type 1 collagen in the determination of CCT in both OI patients and normal individuals. This provides the first evidence of quantitative trait loci that influence CCT in a normal population and has potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia. david.dimasi@flinders.edu.au
authors.forename: David P
authors.initials: DP
authors.lastname: Dimasi
authors.forename: Jern Y
authors.initials: JY
authors.lastname: Chen
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.forename: Sonja
authors.initials: S
authors.lastname: Klebe
authors.forename: Richard
authors.initials: R
authors.lastname: Davey
authors.forename: John
authors.initials: J
authors.lastname: Stirling
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.forename: Robin
authors.initials: R
authors.lastname: Forbes
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000818:Animals; D001315:Australia; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003315:Cornea / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D019781:Corneal Topography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003094:Collagen