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Xiaohui Li, Yelena Bykhovskaya, Talin Haritunians, David Siscovick, Anthony J. Aldave, Loretta B. Szczotka-Flynn, Sudha K. Iyengar, Jerome I. Rotter, Kent D. Taylor, Yaron S. Rabinowitz; Evidence For Association Between COL5A1 SNPs Associated With Central Corneal Thickness And Keratoconus. Invest. Ophthalmol. Vis. Sci. 2012;53(14):79.
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Several genome-wide association studies (GWASs) of central corneal thickness (CCT) have identified genome-wide significant associations for single nucleotide polymorphisms (SNPs) located near or within the collagen, type V, alpha 1, gene (COL5A1), which has been mapped to 9q34.2-q34.3. Given the fact that in a previous genome-wide linkage study of keratoconus families, we identified a maximum LOD score of 2.7 at 9q34, we examined the results of association tests between this gene and keratoconus in two independent case-control cohorts and a family sample.
GWAS was performed using Illumina 370K beadchips in a discovery panel of 222 local Caucasian keratoconus patients and 3324 controls from the Cardiovascular Health Study (CHS). Replication of positively associated SNPs was performed in an independent case-control panel (304 cases from three centers and 518 local controls) and a local family panel (186 subjects in 41 families). Logistic regression models with adjustments for principal components implemented in PLINK were used to test for association in case-control samples. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families.
Two SNPs, located near or in COL5A1 gene, rs1536482 (OR=1.32, p=6.5×10-3) and rs7044529 (OR=1.44, p=7.4×10-3) were identified in the GWAS discovery cohort. Replication in the case-control samples confirmed association with rs1536482 (OR=1.28, p=0.02), but not with rs7044529 (OR=1.02, p=0.92). Replication in the family samples confirmed a significant association with rs7044529 (OR=1.96, p=0.03) and yielded a similar yet not significant association for rs1536482 (OR=1.27, p=0.20). The meta p values of rs1536482 and rs7044529 combining three keratoconus cohorts were 1.5×10-4 (OR=1.30) and 2.9×10-3 (OR=1.39), respectively. Interestingly, both of these SNPs have been reported to be associated with CCT: rs1536482 in Caucasian populations with a p value of 7.1×10-8 and rs7044529 in both Caucasians and Asians with a meta p of 1.0x10-8.
SNPs in COL5A1, which regulate normal variation in CCT, may also play a role in the corneal thinning in keratoconus.
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