Gurung Rajya L, Nangia Charvi, Cai Tengda, FitzGerald Liesel M, McComish Bennet J, Liu Ebony, Kaidonis Georgia, Ridge Bronwyn, Hewitt Alex W, Vote Brendan, Verma Nitin, Craig Jamie E, Palmer Colin N A, Burdon Kathryn P, Meng Weihua
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Division of Population Health and Genomics, Ninewells Hospital, School of Medicine, University of Dundee, Dundee, United Kingdom.
Invest Ophthalmol Vis Sci. 2025 Mar 3;66(3):55. doi: 10.1167/iovs.66.3.55.
Diabetic maculopathy (including diabetic macular edema [DME]) is the leading cause of vision loss in people with diabetes. We aimed to identify the genetic determinants of diabetic maculopathy.
We conducted a genome-wide association study (GWAS) in two cohorts with a meta-analysis. The Australian cohort comprised 551 cases of DME and 599 controls recruited from the states of South Australia and Tasmania. The Scottish cohort comprised 1951 cases of diabetic maculopathy and 6541 controls from the Genetics of Diabetes Audit and Research in Tayside Scotland study (GoDARTS). Genotyping, imputation, and association analysis using logistic regression were conducted in each cohort, before combining summary statistics in a meta-analysis using the GWAMA package.
A locus on chromosome 7 reached genome-wide significance in GoDARTS but showed the opposite direction of effect in the Australian cohort. The meta-analysis identified two suggestive associations (P < 5 × 10-6) for diabetic maculopathy risk with similar effect direction; one at chromosome 1 close to the RNU5E-1 gene and one at chromosome 13 upstream of the ERICH6B gene. The two loci were evaluated in silico for potential functional links to diabetic maculopathy. Both are located in regulatory regions and have annotations indicating regulatory functions. They are also expression quantitative trait locus (eQTLs) for genes plausibly involved in diabetic maculopathy pathogenesis, with links to folate metabolism and the regulation of VEGF.
The study suggests several promising SNPs and genes related to diabetic maculopathy risk. Despite being the largest genetic study of diabetic maculopathy to date, larger, homogeneous cohorts will be required to identify robust genetic risk loci for the disease.
糖尿病性黄斑病变（包括糖尿病性黄斑水肿[DME]）是糖尿病患者视力丧失的主要原因。我们旨在确定糖尿病性黄斑病变的遗传决定因素。
我们在两个队列中进行了全基因组关联研究（GWAS）并进行了荟萃分析。澳大利亚队列包括从南澳大利亚州和塔斯马尼亚州招募的551例DME患者和599名对照。苏格兰队列包括来自苏格兰泰赛德糖尿病遗传审计与研究（GoDARTS）的1951例糖尿病性黄斑病变患者和6541名对照。在每个队列中进行基因分型、归因和使用逻辑回归的关联分析，然后使用GWAMA软件包在荟萃分析中合并汇总统计数据。
7号染色体上的一个位点在GoDARTS中达到全基因组显著性，但在澳大利亚队列中显示出相反的效应方向。荟萃分析确定了两个与糖尿病性黄斑病变风险相关的提示性关联（P < 5×10-6），效应方向相似；一个在1号染色体上靠近RNU5E-1基因的位置，另一个在13号染色体上ERICH6B基因的上游。对这两个位点进行了计算机模拟评估，以确定与糖尿病性黄斑病变的潜在功能联系。两者都位于调控区域，并有表明调控功能的注释。它们也是可能参与糖尿病性黄斑病变发病机制的基因的表达数量性状位点（eQTL），与叶酸代谢和VEGF的调节有关。
该研究提示了几个与糖尿病性黄斑病变风险相关的有前景的单核苷酸多态性（SNP）和基因。尽管这是迄今为止关于糖尿病性黄斑病变的最大规模遗传研究，但仍需要更大规模、同质化的队列来确定该疾病可靠的遗传风险位点。
