Gurung Rajya L, FitzGerald Liesel M, Liu Ebony, McComish Bennet J, Kaidonis Georgia, Ridge Bronwyn, Hewitt Alex W, Vote Brendan J, Verma Nitin, Craig Jamie E, Burdon Kathryn P
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
Department of Ophthalmology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia.
Int J Mol Sci. 2022 Apr 6;23(7):4042. doi: 10.3390/ijms23074042.
Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
眼内抗血管内皮生长因子（VEGF）疗法是糖尿病性黄斑水肿（DME）的一线治疗方法；然而，治疗反应差异很大。本研究旨在确定与DME抗VEGF治疗反应相关的遗传决定因素。我们对220名接受抗VEGF治疗的澳大利亚DME患者进行了全基因组关联研究，在Illumina全球筛查阵列上进行基因分型，并推算到单倍型参考联盟面板。主要结局指标是12个月后中心黄斑厚度（以微米为单位的CMT）和最佳矫正视力（以ETDRS字母为单位的BCVA）的变化。通过线性回归评估单核苷酸多态性（SNP）基因型与DME结局之间的关联，并对前三个主成分、年龄、基线CMT/BCVA、糖尿病视网膜病变持续时间和糖化血红蛋白进行校正。两个位点与CMT增加的关联达到全基因组显著性（p < 5 × 10−8）：6号染色体上靠近CASC15的一个单SNP（rs78466540，p = 1.16 × 10−9）和12号染色体上靠近RP11-116D17.1的一个位点（顶级SNP rs11614480，p = 2.69 × 10−8）。四个位点与BCVA降低显著相关：11号染色体上NTM下游的两个位点（顶级SNP rs148980760，p = 5.30 × 10−9）和RP11-744N12.3内含子中的位点（顶级SNP rs57801753，p = 1.71 × 10−8）；5号染色体上靠近PGAM1P1的一个位点（rs187876551，p = 1.52 × 10−8）；以及6号染色体上靠近TBC1D32的一个位点（rs118074968，p = 4.94 × 10−8）。对每个位点的计算机模拟研究确定了多个表达数量性状位点和潜在相关的候选基因，值得进一步分析。因此，我们确定了多个预测DME抗VEGF治疗结局的遗传位点。这项工作可能会潜在地导致使用个性化治疗方法来管理DME。
