Shih Chien-Hung, Chuang Hao-Kai, Hsiao Tzu-Hung, Yang Yi-Ping, Gao Chong-En, Chiou Shih-Hwa, Hsu Chih-Chien, Hwang De-Kuang
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Front Genet. 2023 Feb 24;14:1064659. doi: 10.3389/fgene.2023.1064659. eCollection 2023.
Age-related macular degeneration (AMD) is the main cause of severe vision loss in elderly populations of the developed world with limited therapeutic medications available. It is a multifactorial disease with a strong genetic susceptibility which exhibits the differential genetic landscapes among different ethnic groups. To investigate the Han Chinese-specific genetic variants for AMD development and progression, we have presented a genome-wide association study (GWAS) on 339 AMD cases and 3,390 controls of a Han Chinese population recruited from the Taiwan Precision Medicine Initiative (TPMI). In this study, we have identified several single nucleotide polymorphisms (SNPs) significantly associated with AMD, including rs10490924, rs3750848, and rs3750846 in the ARMS2 gene, and rs3793917, rs11200638, and rs2284665 in the HTRA1 gene, in which rs10490924 was highly linked to the other variants based upon linkage disequilibrium analysis. Moreover, certain systemic comorbidities, including chronic respiratory diseases and cerebrovascular diseases, were also confirmed to be independently associated with AMD. Stratified analysis revealed that both non-exudative and exudative AMD were significantly correlated with these risk factors. We also found that homozygous alternate alleles of rs10490924 could lead to an increased risk of AMD incidence compared to homozygous references or heterozygous alleles in the cohorts of chronic respiratory disease, cerebrovascular disease, hypertension, and hyperlipidemia. Ultimately, we established the SNP models for AMD risk prediction and found that rs10490924 combined with the other AMD-associated SNPs identified from GWAS improved the prediction model performance. These results suggest that genetic variants combined with the comorbidities could effectively identify any potential individuals at a high risk of AMD, thus allowing for both early prevention and treatment.
年龄相关性黄斑变性（AMD）是发达国家老年人群严重视力丧失的主要原因，且可用的治疗药物有限。它是一种多因素疾病，具有很强的遗传易感性，在不同种族群体中表现出不同的遗传特征。为了研究汉族人群中与AMD发生和发展相关的特定基因变异，我们对从台湾精准医学计划（TPMI）招募的339例AMD患者和3390例汉族对照进行了全基因组关联研究（GWAS）。在这项研究中，我们鉴定了几个与AMD显著相关的单核苷酸多态性（SNP），包括ARMS2基因中的rs10490924、rs3750848和rs3750846，以及HTRA1基因中的rs3793917、rs11200638和rs2284665，其中基于连锁不平衡分析，rs10490924与其他变异高度连锁。此外，某些全身性合并症，包括慢性呼吸道疾病和脑血管疾病，也被证实与AMD独立相关。分层分析显示，非渗出性和渗出性AMD均与这些风险因素显著相关。我们还发现，在慢性呼吸道疾病、脑血管疾病、高血压和高脂血症队列中，rs10490924的纯合替代等位基因与纯合参考等位基因或杂合等位基因相比，会导致AMD发病风险增加。最终，我们建立了AMD风险预测的SNP模型，发现rs10490924与从GWAS中鉴定出的其他AMD相关SNP相结合可提高预测模型的性能。这些结果表明，基因变异与合并症相结合可以有效地识别任何潜在的AMD高危个体，从而实现早期预防和治疗。
