Translational Genomics Laboratory, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan.
Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
Acta Diabetol. 2020 Feb;57(2):237-245. doi: 10.1007/s00592-019-01407-5. Epub 2019 Aug 31.
The incidence of microvascular complications, including diabetic retinopathy (DR), increases with duration of type 2 diabetes (T2D). Meta-GWAS have reported numerous single-nucleotide polymorphisms (SNPs) associated with T2D; however, no loci, achieving genome-wide significance has been reported for DR. Vascular endothelial growth factor A (VEGFA) and insulin-like growth factor 1 (IGF1) are considered as potential genetic candidates involved in T2D and DR progression. Moreover, the association of serum levels of these proteins with diabetes-related traits is controversial. Therefore, the current study was designed to evaluate the possible genetic predisposition and role of these circulating growth factors in serum in the pathophysiology of T2D and DR.
A cohort of 1126 individuals with T2D was collected including those without retinopathy (DNR = 573), non-progressive diabetic retinopathy (NPDR = 301) and progressive diabetic retinopathy (PDR = 252), and 348 healthy controls. Genomic DNA was isolated, and six SNPs: rs833061, rs13207351, rs1570360, rs2010963, rs5742632 and rs6214, were genotyped and results statistically analyzed. ELISA was performed on a subset of the samples to measure serum levels of IGF1 and VEGFA.
The minor allele of rs6214 was associated with T2D [OR = 1.67 (95% CI 1.39-2.01, p = 4.9E-8)], rs13207351 was associated with NPDR [OR = 1.97 (95% CI 1.28-3.03, p = 9.0E-3)]when compared with DNR, and rs5742632 showed positive association with PDR [OR = 1.66 (95% CI 1.33-2.05, p = 1.0E-4)] compared to DNR. Lowered IGF1 serum levels were found to be associated with T2D, NPDR and PDR.
IGF1 was found to increase the T2DM susceptibility as well as advanced DR, i.e., PDR, while VEGFA was found to be associated with early DR stage, i.e., NPDR.
微血管并发症的发生率，包括糖尿病视网膜病变（DR），随着 2 型糖尿病（T2D）的持续时间而增加。荟萃 GWAS 已报道了许多与 T2D 相关的单核苷酸多态性（SNP）；然而，没有发现与 DR 相关的达到全基因组显著性的位点。血管内皮生长因子 A（VEGFA）和胰岛素样生长因子 1（IGF1）被认为是参与 T2D 和 DR 进展的潜在遗传候选物。此外，这些蛋白质的血清水平与糖尿病相关特征的关联存在争议。因此，本研究旨在评估这些循环生长因子在血清中的遗传易感性和作用在 T2D 和 DR 病理生理学中的可能作用。
收集了 1126 名 T2D 患者的队列，包括无视网膜病变（DNR=573）、非进行性糖尿病视网膜病变（NPDR=301）和进行性糖尿病视网膜病变（PDR=252），以及 348 名健康对照。分离基因组 DNA，并对六个 SNP：rs833061、rs13207351、rs1570360、rs2010963、rs5742632 和 rs6214 进行基因分型，并对结果进行统计学分析。对部分样本进行 ELISA 以测量 IGF1 和 VEGFA 的血清水平。
rs6214 的次要等位基因与 T2D 相关[OR=1.67（95% CI 1.39-2.01，p=4.9E-8）]，rs13207351 与 NPDR 相关[OR=1.97（95% CI 1.28-3.03，p=9.0E-3)]与 DNR 相比，rs5742632 与 PDR 呈正相关[OR=1.66（95% CI 1.33-2.05，p=1.0E-4)]与 DNR 相比。发现 IGF1 血清水平降低与 T2D、NPDR 和 PDR 相关。
发现 IGF1 增加了 T2DM 的易感性以及进展性 DR，即 PDR，而 VEGFA 与早期 DR 阶段，即 NPDR 相关。
