Medicine Biomedical Genetics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2011;6(10):e25775. doi: 10.1371/journal.pone.0025775. Epub 2011 Oct 6.
ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6 × 10(-4)) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.
ROBO1 是年龄相关性黄斑变性 (AMD) 的一个强有力的候选基因，这是基于其位于染色体 3p12 的连锁峰下的位置、其表达模式以及其在包括 RORA 的途径中的假定功能，RORA 是先前与新生血管性 AMD 风险相关的基因。此前，我们观察到与未受影响的同胞相比，ROBO1 和 RORA 的表达在湿性 AMD 病例中下调。因此，我们假设 ROBO1 中的关联信号的贡献以及这两个基因之间的相互作用可能对湿型和干型 AMD 都很重要。我们在一个同胞队列和一个包含 491 例湿性 AMD 病例、174 例干性 AMD 病例和 411 例对照的希腊病例对照队列中评估了 ROBO1 中的 19 个单核苷酸多态性 (SNP) 与 AMD 湿型和干型阶段的关联。关联信号和相互作用结果在一个独立的前瞻性队列 (1070 例对照、164 例湿性 AMD 病例、293 例干性 AMD 病例) 中得到了复制。在加性模型下，与湿性 AMD 最显著相关的 ROBO1 SNP 是 rs1387665(meta P = 0.028)，在隐性模型下，与干性 AMD 最显著相关的 SNP 是 rs9309833(meta P = 6 × 10(-4))。进一步的分析揭示了 ROBO1 rs9309833 与 RORA rs8034864 之间在湿性和干性 AMD 中的相互作用 (interaction P<0.05)。这些研究进一步得到了 66 只人供体眼的全转录组表达谱研究和来自小鼠视网膜的染色质免疫沉淀测定的支持。这些发现表明，不同的 ROBO1 变体可能影响湿性和干性 AMD 的风险，而 ROBO1 对 AMD 风险的影响可能受 RORA 变体的调节。
