Novel quantitative trait loci for central corneal thickness identified by candidate gene analysis of osteogenesis imperfecta genes.
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.
Dimasi
David P
DP
Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia. david.dimasi@flinders.edu.au
Chen
Jern Y
JY
Hewitt
Alex W
AW
Klebe
Sonja
S
Davey
Richard
R
Stirling
John
J
Thompson
Elizabeth
E
Forbes
Robin
R
Tan
Tiong Y
TY
Savarirayan
Ravi
R
Mackey
David A
DA
Healey
Paul R
PR
Mitchell
Paul
P
Burdon
Kathryn P
KP
Craig
Jamie E
JE
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*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003094:Collagen