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B. Fan, L. R. Pasquale, C. L. Grosskreutz, T. Chen, D. Rhee, E. A. DelBono, J. L. Haines, J. L. Wiggs; Contribution of the CBS Gene to Pseudoexfoliation Glaucoma and Interaction With LOXL1. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1721. doi: https://doi.org/.
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Pseudoexfoliation syndrome (PXF) and primary open-angle glaucoma (POAG) are two major causes of glaucoma. Recently, a genome-wide association study identified a strong association of the LOXL1 gene with PXF in patients from Iceland and Sweden. This association has been replicated in our study of U.S. clinic-based population with broad ethnic diversity and other studies in Caucasian populations. However, the risk haplotype of LOXL1 is also prevalent in control samples. It indicates additional genetic factors and/or environmental exposures could be involved in the development of this complex disease. In the present study, we investigated LOXL1 and an additional 9 genes that are potential candidates for PXF based on biological and functional data in a case-control sample.
A total of 17 SNPs in 10 genes (CBS, DPP10, ELN, LOXL1, LOXL3, MTHFD1, MTHFR, MTR, MTRR and TRIM62) were genotyped in a sample of 206 PXF, 325 POAG and 88 controls. Single-SNP association was analyzed using a chi-squared test. Pairwise-SNP interaction analysis was performed using PLINK. Multiple comparisons were corrected by the Bonferroni method.
Two non-synonymous SNPs (rs3825942, G153D; rs1048661, R141L) and an intronic SNP (rs2165241) in LOXL1 were significantly associated with PXF (p = 4.9×10-17, 0.003, 4.4×10-12, respectively) but not with POAG (p > 0.31). Two coding SNPs (rs1801181, A360A; rs5742905, I278T) in CBS demonstrated a strong association with PXF (p = 2.2×10-6 and 0.007 respectively) and with POAG (p = 0.006 and 0.02 respectively). Intriguingly, two LOXL1 SNPs (rs2165241 and rs1048661) showed an interactive effect on PXF with a CBS SNP (rs1801181) (p = 0.0049 and 0.046 respectively). Meanwhile, rs1801181 significantly interacted with a MTHFD1 SNP (rs2236225) (p = 0.01) in contributions to PXF development.
We have identified two new genes (CBS and MTHFD1) that might contribute to PXF interactively with LOXL1. Interestingly, both of these genes function in the regulation of homocysteine metabolism, another factor that has been implicated in PXF. Further functional studies and replication studies are needed to confirm our findings.
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