Department of Ophthalmology and Visual Sciences, The University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
BMC Med Genet. 2011 Apr 26;12:58. doi: 10.1186/1471-2350-12-58.
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.
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.
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).
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.
年龄相关性黄斑变性（AMD）是一种常见的老年疾病，可导致由于萎缩或新生血管事件而导致中央视野丧失。来自人眼和动物模型的证据表明，巨噬细胞和内皮细胞激活在 AMD 的发病机制中起着重要作用。我们试图确定编码选择素家族蛋白的基因中的常见祖先变异是否与 AMD 相关。
通过定量 PCR 和免疫荧光法检查脉络膜和视网膜中 E-选择素、L-选择素和 P-选择素的表达。对 341 名 AMD 患者（n=341）和 400 名对照（n=400）的样本进行了总共 34 个 SELE、SELL 和 SELP 基因中的 SNP 基因分型。比较 AMD 患者与对照组之间以及 AMD 各亚型（干性、地理萎缩和湿性）与对照组之间这些 SNP 的等位基因和基因型频率。
与视网膜相比，三种选择素基因在脉络膜中的表达均较高。观察到视网膜小胶质细胞、玻璃膜疣核心和脉络膜血管的某些选择素标记。在 AMD 与对照组的遗传筛查中，SELE 或 SELL 均未显示出阳性关联。SELp 中的一个 SNP（rs3917751）产生了 <0.05 的 p 值（未经多重测量校正）。在亚型分析中，6 个 SNP（SELE 中的一个、SELL 中的两个和 SELP 中的三个）产生了 <0.05 的 p 值。然而，当用 Bonferroni 校正进行多重测量校正时，SELp 中的一个 SNP（rs3917751）仅产生统计学上显著的 p 值（p=0.0029）。
该遗传筛查未检测到与 AMD 总体发病状态高度相关的任何 SNP。然而，亚型分析表明，位于 SELP 内含子内的单个 SNP（rs3917751）与我们队列中的干性 AMD 具有统计学关联。具有额外队列和功能测定的未来研究将阐明这一发现的生物学意义。根据我们的发现，SELE 和 SELL 中常见的祖先变异不太可能是 AMD 的危险因素。最后，SELE、SELL 或 SELP 中的散发性或罕见突变在 AMD 的发病机制中可能起作用。
