SanGiovanni John Paul, Chen Jing, Gupta Ankur S, Smith Lois E H, Sapieha Przemyslaw, Lee Phil H
National Institute of Alcohol Abuse and Alcoholism, Section on Nutritional Neuroscience, National Institutes of Health, Bethesda, MD, United States of America.
Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States of America.
PLoS One. 2015 May 7;10(5):e0125548. doi: 10.1371/journal.pone.0125548. eCollection 2015.
We conducted a nested candidate gene study and pathway-based enrichment analysis on data from a multi-national 77,000-person project on the molecular genetics of age-related macular degeneration (AMD) to identify AMD-associated DNA-sequence variants in genes encoding constituents of a netrin-1 (NTN1)-based signaling pathway that converges on DNA-binding transcription complexes through a 3'-5'-cyclic adenosine monophosphate-calcineurin (cAMP-CN)-dependent axis. AMD-associated single nucleotide polymorphisms (SNPs) existed in 9 linkage disequilibrium-independent genomic regions; these included loci overlapping NTN1 (rs9899630, P ≤ 9.48 x 10(-5)), DCC (Deleted in Colorectal Cancer)--the gene encoding a primary NTN1 receptor (rs8097127, P ≤ 3.03 x 10(-5)), and 6 other netrin-related genes. Analysis of the NTN1-DCC pathway with exact methods demonstrated robust enrichment with AMD-associated SNPs (corrected P-value = 0.038), supporting the idea that processes driven by NTN1-DCC signaling systems operate in advanced AMD. The NTN1-DCC pathway contains targets of FDA-approved drugs and may offer promise for guiding applied clinical research on preventive and therapeutic interventions for AMD.
我们对一项关于年龄相关性黄斑变性（AMD）分子遗传学的多国77000人项目的数据进行了巢式候选基因研究和基于通路的富集分析，以识别编码基于netrin-1（NTN1）的信号通路成分的基因中的AMD相关DNA序列变异，该信号通路通过3'-5'-环磷酸腺苷-钙调神经磷酸酶（cAMP-CN）依赖性轴汇聚于DNA结合转录复合物。AMD相关单核苷酸多态性（SNP）存在于9个连锁不平衡独立的基因组区域；这些区域包括与NTN1重叠的位点（rs9899630，P≤9.48×10⁻⁵）、DCC（结直肠癌缺失基因）——编码主要NTN1受体的基因（rs8097127，P≤3.03×10⁻⁵）以及其他6个与netrin相关的基因。用精确方法对NTN1-DCC通路进行分析，结果显示AMD相关SNP有显著富集（校正P值 = 0.038），这支持了NTN1-DCC信号系统驱动的过程在晚期AMD中起作用的观点。NTN1-DCC通路包含FDA批准药物的靶点，可能为指导AMD预防和治疗干预的应用临床研究带来希望。
