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Ha Ae Bae, Richard A. D. Mills, Richard G. Lindsay, Tony Phillips, Douglas J. Coster, Paul Mitchell, Jie Jin Wang, Jamie E. Craig, Kathryn P. Burdon; Replication and Meta-Analysis of Candidate Loci Identified Variation at RAB3GAP1 Associated With Keratoconus. Invest. Ophthalmol. Vis. Sci. 2013;54(7):5132-5135. doi: 10.1167/iovs.13-12377.
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Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.
We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.
Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 × 10−9 passing the genome-wide significance level.
Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.
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