Fleckenstein Monika, Grassmann Felix, Lindner Moritz, Pfau Maximilian, Czauderna Joanna, Strunz Tobias, von Strachwitz Claudia, Schmitz-Valckenberg Steffen, Holz Frank G, Weber Bernhard H F
Department of Ophthalmology University of Bonn, Bonn, Germany.
Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Invest Ophthalmol Vis Sci. 2016 May 1;57(6):2463-71. doi: 10.1167/iovs.15-18593.
To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging.
Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffuse-trickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/intron boundaries were sequenced.
A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH:rs1061170 and CFH:rs800292 (Pcorrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (Pcorrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (Pcorrected <0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals.
The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD.
对年龄相关性黄斑变性（AMD）中与快速进展及眼底自发荧光成像上的弥漫性细流样外观相关的地图样萎缩（GA）亚表型进行基因特征分析。
年龄相关性黄斑变性研究中眼底自发荧光的患者被进行弥漫性细流样GA（dt-GA；n = 44）的表型分析。对10个已知的AMD相关基因变异进行DNA分析。计算遗传风险评分（GRS），并与非弥漫性细流样GA（ndt-GA；n = 311）患者及千人基因组计划（1000G；n = 267）的个体进行比较。鉴于弥漫性细流样与迟发性视网膜变性（LORD）之间的表型重叠，对所有C1QTNF5外显子及其外显子/内含子边界进行测序。
CFH:rs1061170和CFH:rs800292在dt-GA和ndt-GA之间的等位基因频率存在统计学显著差异（校正P = 0.03）。ARMS2变异rs10490924在dt-GA中比在1000G个体中显著更常见（校正P < 0.01）。dt-GA患者的GRS介于1000G个体和ndt-GA患者的评分之间，与两者均有显著差异（校正P <0.01）。C1QTNF5测序揭示了28个独特变异，但与1000G个体相比，没有一个与dt-GA显示出统计学显著关联。
dt-GA表型显示出与继发于AMD的其他GA表型明显不同的遗传风险特征。未鉴定出与疾病相关的C1QTNF5突变。总之，这些结果表明dt-GA表型与与其他GA表型有很大不同的遗传背景相关，并强调了细化临床表型分析的必要性，特别是在针对AMD个体化治疗时。
