AIBILI-Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal.
Ophthalmology Department, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
Invest Ophthalmol Vis Sci. 2022 Aug 2;63(9):5. doi: 10.1167/iovs.63.9.5.
To determine the association between rare genetic variants in complement factor H (CFH) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES).
AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced through single-molecule molecular inversion probe-based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations.
We included 39 eyes of 23 patients carrying rare CFH variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61-18.37]; P = 0.006), outer circle (OR, 4.37 [95% CI, 1.07-17.77]; P = 0.04), and full grid (OR, 4.82 [95% CI, 1.13-20.52]; P = 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers' volume (OR, 0.449 [95% CI, 0.226-0.894]; P = 0.023; OR, 0.496 [95% CI, 0.252-0.979]; P = 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08-25.44]; P = 0.04) were associated with carrying a rare CFH variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one.
We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the CFH gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.
在 Coimbra 眼病研究（CES）中，确定补体因子 H（CFH）中的罕见遗传变异与年龄相关性黄斑变性（AMD）患者表型特征之间的关联。
来自发病 CES 的 AMD 患者（NCT02748824）接受眼科检查和眼底彩色摄影、光谱域光学相干断层扫描（SD-OCT）、眼底自发荧光和近红外成像。在一个集中的阅读中心进行多模态表型特征分析。通过基于单分子分子反转探针的下一代测序，对 CFH 基因的编码和剪接区域进行测序，同时与 EYE-RISK 联盟合作。选择等位基因频率<0.05 的导致剪接或蛋白改变的变异。使用广义估计方程逻辑回归模型分析携带和不携带罕见 CFH 变异的患者之间表型特征的差异，同时考虑到眼间相关性。
我们纳入了 39 只携带罕见 CFH 变异的 23 名患者的眼睛和 284 只不携带罕见 CFH 变异的 188 名患者的眼睛。携带状态与内早期治疗糖尿病视网膜病变研究（ETDRS）圆圈内侧（优势比 [OR]，5.44 [95%置信区间 {CI}，1.61-18.37]；P = 0.006）、外侧圆圈（OR，4.37 [95% CI，1.07-17.77]；P = 0.04）和全网格（OR，4.82 [95% CI，1.13-20.52]；P = 0.033）中更高的玻璃膜疣负担有关。在 SD-OCT 中，总黄斑体积和内层视网膜体积较低（OR，0.449 [95% CI，0.226-0.894]；P = 0.023；OR，0.496 [95% CI，0.252-0.979]；P = 0.043）和色素上皮脱离（PED）（OR，5.24 [95% CI，1.08-25.44]；P = 0.04）与携带罕见 CFH 变异有关。除了一例外，携带视网膜下类脂沉积（SDD）的患者均携带罕见变异 P258L。
在我们的队列中，我们发现了 CFH 基因罕见变异携带者和非携带者之间的表型差异。携带者的疾病更严重，即玻璃膜疣负担更高、PED 和视网膜更薄。罕见变异 P258L 可能与 SDD 有关。携带者可能有更高的进展风险。
