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.

Identification and molecular characterization of two novel mutations in COL1A2 in two Chinese families with osteogenesis imperfecta

“…It is well-known that the severity of OI varies even among patients in the same family Witecka et al, 2008;Basel and Steiner, 2009;Brooks et al, 2009;Dimasi et al, 2010). In this study, phenotypic variability was also observed between family 1 and family 2 as well as among patients in each family.…”

Genome-Wide Analysis of Central Corneal Thickness in Primary Open-Angle Glaucoma Cases in the NEIGHBOR and GLAUGEN Consortia

“…A reduction in central corneal thickness (CCT) has been observed in a number of systemic and ocular diseases, including Ehlers-Danlos syndrome, osteogenesis imperfecta, keratoconus, and brittle cornea syndrome. [1][2][3][4] Reduced CCT has also been associated with an increased risk of primary open-angle glaucoma (POAG), the second leading cause of blindness worldwide. 5,6 In POAG, CCT has been shown to be a risk factor independent of other known risk factors, including advanced age and elevated intraocular pressure (IOP), and has been linked with increased disease severity and rapid disease progression.…”

Genome-wide association study identifiesWNT7Bas a novel locus for central corneal thickness in Latinos

“…Mounting evidence suggests central corneal thickness (CCT) plays a significant factor in ocular health. Thin CCT has been observed in several visual disorders, including brittle cornea syndrome, keratoconus, and osteogenesis imperfecta (1)(2)(3). CCT is also an important endophenotype for primary open angle glaucoma (POAG).…”