全基因组生存分析揭示中心性浆液性脉络膜视网膜病变中脉络膜新生血管发展与息肉样脉络膜血管病变具有共同的遗传易感性。

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy.

机构信息

Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

出版信息

Ophthalmology. 2022 Sep;129(9):1034-1042. doi: 10.1016/j.ophtha.2022.04.018. Epub 2022 Apr 29.

DOI:10.1016/j.ophtha.2022.04.018

PMID:35490733

Abstract

PURPOSE

To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC).

DESIGN

Genome-wide survival analysis using a longitudinal cohort study.

PARTICIPANTS

We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography.

METHODS

We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0 × 10 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis.

MAIN OUTCOME MEASURES

The association between SNPs and MNV development in patients with CSC.

RESULTS

Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR], 3.63; P = 5.76 × 10). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P = 2.55 × 10), COL4A3 rs4276018 (HR, 0.26, P = 1.56 × 10), and B3GALTL rs9564692 (HR, 0.56, P = 8.30 × 10) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport.

CONCLUSIONS

ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

摘要

目的

鉴定中心性浆液性脉络膜视网膜病变（CSC）中导致黄斑新生血管（MNV）发展的易感性基因。

设计

使用纵向队列研究进行全基因组生存分析。

参与者

我们分别纳入了来自京都 CSC 队列和神户 CSC 数据集的首次就诊时无 MNV 的 402 例和 137 例 CSC 患者。所有患者均接受了详细的眼科检查，包括多模态成像，如眼底自发荧光、谱域 OCT 和荧光素血管造影/吲哚青绿血管造影或 OCT 血管造影。

方法

我们使用京都 CSC 队列进行了全基因组生存分析。我们应用 Cox 比例风险模型来调整年龄、性别和第一主成分。将 P 值<1.0×10 的单核苷酸多态性（SNP）推进到神户 CSC 数据集的复制中。此外，我们评估了先前报道的年龄相关性黄斑变性（AMD）易感性基因座的贡献。我们使用 FUMA 和 ToppFun 进行功能富集分析。

主要观察指标

SNP 与 CSC 患者 MNV 发展之间的关联。

结果

在发现和复制结果的荟萃分析中，ARMS2 附近的 rs370974631 显示出全基因组显著关联（风险比[HR]，3.63；P=5.76×10）。在先前报道的 AMD 易感性基因座中，我们还鉴定出 CFH rs800292（HR，0.39，P=2.55×10）、COL4A3 rs4276018（HR，0.26，P=1.56×10）和 B3GALTL rs9564692（HR，0.56，P=8.30×10）作为 CSC 中 MNV 发展的易感性基因座。功能富集分析显示，与离子转运相关的 8 条途径（GO：0051561、GO：0036444、GO：0008282、GO：1990246、GO：0015272、GO：0030955、GO：0031420 和 GO：0005242）存在显著富集。

结论

鉴定出 ARMS2、CFH、COL4A3 和 B3GALTL 是 CSC 中 MNV 发展的易感性基因。这 4 个基因是已知的 AMD 易感性基因，而 COL4A3 和 B3GALTL 先前被报道为息肉样脉络膜血管病变（PCV）特异性易感性基因。我们的研究结果揭示了 PCV 和 MNV 继发性 CSC 之间的共同遗传易感性。