Evaluation of variants in the selectin genes in age-related macular degeneration

BACKGROUND: Age-related macular degeneration (AMD) is a common disease of the elderly that leads to loss of the central visual field due to atrophic or neovascular events. Evidence from human eyes and animal models suggests an important role for macrophages and endothelial cell activation in the pathogenesis of AMD. We sought to determine whether common ancestral variants in genes encoding the selectin family of proteins are associated with AMD. METHODS: Expression of E-selectin, L-selectin and P-selectin was examined in choroid and retina by quantitative PCR and immunofluorescence. Samples from patients with AMD (n = 341) and controls (n = 400) were genotyped at a total of 34 SNPs in the SELE, SELL and SELP genes. Allele and genotype frequencies at these SNPs were compared between AMD patients and controls as well as between subtypes of AMD (dry, geographic atrophy, and wet) and controls. RESULTS: High expression of all three selectin genes was observed in the choroid as compared to the retina. Some selectin labeling of retinal microglia, drusen cores and the choroidal vasculature was observed. In the genetic screen of AMD versus controls, no positive associations were observed for SELE or SELL. One SNP in SELP (rs3917751) produced p-values < 0.05 (uncorrected for multiple measures). In the subtype analyses, 6 SNPs (one in SELE, two in SELL, and three in SELP) produced p-values < 0.05. However, when adjusted for multiple measures with a Bonferroni correction, only one SNP in SELP (rs3917751) produced a statistically significant p-value (p = 0.0029). CONCLUSIONS: This genetic screen did not detect any SNPs that were highly associated with AMD affection status overall. However, subtype analysis showed that a single SNP located within an intron of SELP (rs3917751) is statistically associated with dry AMD in our cohort. Future studies with additional cohorts and functional assays will clarify the biological significance of this discovery. Based on our findings, it is unlikely that common ancestral variants in the other selectin genes (SELE and SELL) are risk factors for AMD. Finally, it remains possible that sporadic or rare mutations in SELE, SELL, or SELP have a role in the pathogenesis of AMD.